Amidoaromatic ring sulfonamide hydroxamic acid compounds

ABSTRACT

An amidoaromatic ring sulfonamide hydroxamic acid compound that inter alia inhibits matrix metalloprotease activity is disclosed, as are a treatment process that comprises administering a contemplated amidoaromatic ring sulfonamide hydroxamic acid compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

PRIORITY CLAIM TO RELATED PATENT APPLICATIONS

This patent claims priority as a national-phase application of PCTPatent Application No. PCT/US98/04299 (Int'l Filing Date Mar. 4, 1998;WIPO Int'l Publ. No. WO 98/39329; Int'l Publ. Date Sep. 11, 1998 (inEnglish)), which, in turn, claims priority to U.S. Provisional PatentApplication Serial No. 60/039,795 (filed Mar. 4, 1997). The entire textsof both those patent applications are incorporated by reference intothis patent.

DESCRIPTION

1. Technical Field

This invention is directed to proteinase (protease) inhibitors, and moreparticularly to amidoaromatic ring sulfonamide hydroxamic acid compoundsthat, inter alia, exhibit activity as inhibitors for matrixmetalloproteinases, compositions of proteinase inhibitors, intermediatesfor the syntheses of proteinase inhibitors, processes for thepreparation of proteinase inhibitors and processes for treatingpathological conditions associated with pathological matrixmetalloproteinase-activity.

2. Background of the Invention

Connective tissue, extracellular matrix constituents and basementmembranes are required components of all mammals. These components arethe biological materials that provide rigidity, differentiation,attachments and, in some cases, elasticity to biological systemsincluding human beings and other mammals. Connective tissues componentsinclude, for example, collagen, elastin, proteoglycans, fibronectin andlaminin. These biochemicals makeup, or are components of structures,such as skin, bone, teeth, tendon, cartilage, basement membrane, bloodvessels, cornea and vitreous humor.

Under normal conditions, connective tissue turnover and/or repairprocesses are controlled and in equilibrium. The loss of this balancefor whatever reason leads to a number of disease states. Inhibition ofthe enzymes responsible loss of equilibrium provides a control mechanismfor this tissue decomposition and, therefore, a treatment for thesediseases.

Degradation of connective tissue or connective tissue components iscarried out by the action of proteinase enzymes released from residenttissue cells and/or invading inflammatory or tumor cells. A major classof enzymes involved in this function are the zinc metalloproteinases(metalloproteases).

The metalloprotease enzymes are divided into classes with some membershaving several different names in common use. Examples are: collagenaseI (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8,neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13),stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinaseB (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11),metalloelastase (MMP-12, HME, human macrophage elastase) and membraneMMP (MMP-14). MMP is an abbreviation or acronym representing the termMatrix Metalloprotease with the attached numerals providingdifferentiation between specific members of the MMP group.

The uncontrolled breakdown of connective tissue by metalloproteases is afeature of many pathological conditions. Examples include rheumatoidarthritis, osteoarthritis, septic arthritis; corneal, epidermal orgastric ulceration; tumor metastasis, invasion or angiogenesis;periodontal disease; proteinuria; Alzheimer's Disease; coronarythrombosis and bone disease. Defective injury repair processes alsooccur. This can produce improper wound healing leading to weak repairs,adhesions and scarring. These latter defects can lead to disfigurementand/or permanent disabilities as with post-surgical adhesions.

Matrix metalloproteases are also involved in the biosynthesis of tumornecrosis factor (TNF) and inhibition of the production or action of TNFand related compounds is an important clinical disease treatmentmechanism. TNF-α, for example, is a cytokine that at present is thoughtto be produced initially as a 28 kD cell-associated molecule. It isreleased as an active, 17 kD form that can mediate a large integer ofdeleterious effects in vitro and in vivo. For example, TNF can causeand/or contribute to the effects of inflammation, rheumatoid arthritis,autoimmune disease, multiple sclerosis, graft rejection, fibroticdisease, cancer, infectious diseases, malaria, mycobacterial infection,meningitis, fever, psoriasis, cardiovascular/pulmonary effects such aspost-ischemic reperfusion injury, congestive heart failure, hemorrhage,coagulation, hyperoxic alveolar injury, radiation damage and acute phaseresponses like those seen with infections and sepsis and during shocksuch as septic shock and hemodynamic shock. Chronic release of activeTNF can cause cachexia and anorexia. TNF can be lethal.

TNF-α convertase is a metalloproteinase involved in the formation ofactive TNF-α. Inhibition of TNF-α convertase inhibits production ofactive TNF-α. Compounds that inhibit both MMPs activity have beendisclosed in WIPO International Publication Nos. WO 94/24140, WO94/02466 and WO 97/20824. There remains a need for effective MMP andTNF-α convertase inhibiting agents. Compounds that inhibit MMPs such ascollagenase, stromelysin and gelatinase have been shown to inhibit therelease of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan etal., Nature 376, 558-561 (1994)).

MMPs are involved in other biochemical processes in mammals as well.Included is the control of ovulation, post-partum uterine involution,possibly implantation, cleavage of APP (β-Amyloid Precursor Protein) tothe amyloid plaque and inactivation of α₁-protease inhibitor (α₁-PI).Inhibition of these metalloproteases permits the control of fertilityand the treatment or prevention of Alzheimers Disease. In addition,increasing and maintaining the levels of an endogenous or administeredserine protease inhibitor drug or biochemical such as α₁-PI supports thetreatment and prevention of diseases such as emphysema, pulmonarydiseases, inflammatory diseases and diseases of aging such as loss ofskin or organ stretch and resiliency.

Inhibition of selected MMPs can also be desirable in other instances.Treatment of cancer and/or inhibition of metastasis and/or inhibition ofangiogenesis are examples of approaches to the treatment of diseaseswherein the selective inhibition of stromelysin (MMP-3), gelatinase(MMP-2), or collagenase III (MMP-13) are the relatively most importantenzyme or enzymes to inhibit especially when compared with collagenasd I(MMP-1). A drug that does not inhibit collagenase I can have a superiortherapeutic profile. Osteoarthritis, another prevalent disease whereinit is believed that cartilage degradation in inflamed joints is at leastpartially caused by MMP-13 released from cells such as stimulatedchrondrocytes, may be best treated by administration of drugs one ofwhose modes of action is inhibition of MMP-13. See, for example,Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al.,J. Clin. Invest., 97:2011-2019 (1996).

Inhibitors of metalloproteases are known. Examples include naturalbiochemicals such as tissue inhibitor of metalloproteinase (TIMP),α₂-macroglobulin and their analogs or derivatives. These are highmolecular weight protein molecules that form inactive complexes withmetalloproteases. An integer of smaller peptide-like compounds thatinhibit metalloproteases have been described. Mercaptoamide peptidylderivatives have shown ACE inhibition in vitro and in vivo. Angiotensinconverting enzyme (ACE) aids in the production of angiotensin II, apotent pressor substance in mammals and inhibition of this enzyme leadsto the lowering of blood pressure.

Thiol group-containing amide or peptidyl amide-based metalloprotease(MMP) inhibitors are known as is shown in, for example, WO95/12389,WO96/11209 and U.S. Pat. No. 4,595,700. Hydroxamate group-containing MMPinhibitors are disclosed in a number of published patent applicationssuch as WO 95/29892, WO 97/24117,and EP 0 780 386 that disclose carbonback-boned compounds, and WO 90/05719, WO 93/20047, WO 95/09841 and WO96/06074 that disclose hydroxamates that have a peptidyl back-bones orpeptidomimetic back-bones, as does the article by Schwartz et al.,Progr. Med. Chem., 29:271-334(1992) and those of Rasmussen et al.,Pharmacol. Ther., 75(1): 69-75 (1997) and Denis et al., Invest. NewDrugs, 15(3): 175-185 (1997).

One possible problem associated with known MMP inhibitors is that suchcompounds often exhibit the same or similar inhibitory effects againsteach of the MMP enzymes. For example, the peptidomimetic hydroxamateknown as batimastat is reported to exhibit IC₅₀ values of about 1 toabout 20 nanomolar (nM) against each of MMP-1, MMP-2, MMP-3, MMP-7, andMMP-9. Marimastat, another peptidomimetic hydroxamate was reported to beanother broad-spectrum MMP inhibitor with an enzyme inhibitory spectrumvery similar to batimastat, except that marimastat exhibited an IC₅₀value against MMP-3 of 230 nM. Rasmussen et al., Pharmacol. Ther.,75(1): 69-75 (1997).

Meta analysis of data from Phase I/II studies using marimastat inpatients with advanced, rapidly progressive, treatment-refractory solidtumor cancers (colorectal, pancreatic, ovarian, prostate). indicated adose-related reduction in the rise of cancer-specific antigens used assurrogate markers for biological activity. The most common drug-relatedtoxicity of marimastat in those clinical trials was musculoskeletal painand stiffness, often commencing in the small joints in the hands,spreading to the arms and shoulder. A short dosing holiday of 1-3 weeksfollowed by dosage reduction permits treatment to continue. Rasmussen etal., Pharmacol. Ther., 75(1): 69-75 (1997). It is thought that the lackof specificity of inhibitory effect among the MMPs may be the cause ofthat effect.

In view of the importance of hydroxamate MMP inhibitor compounds in thetreatment of several diseases and the lack of enzyme specificityexhibited by two of the more potent drugs now in clinical trials, itwould be a great benefit if hydroxamates of greater enzyme specificitycould be found. This would be particularly the case if the hydroxamateinhibitors exhibited limited inhibition of MMP-1 that is relativelyubiquitous and as yet not associated with any pathological condition,while exhibiting quite high inhibitory activity against one or more ofMMP-2, MMP-9 or MMP-13 that are associated with several pathologicalconditions. The disclosure that follows describes one family ofhydroxamate MMP inhibitors that exhibit those desirable activities.

BRIEF SUMMARY OF THE INVENTION

The present invention provides compounds and their pharmaceuticallyacceptable salts effective as inhibitors of matrix metalloproteaseenzyme activity; the provision of such compositions that are effectivefor the inhibition of metalloproteases (MMPs) believed to be implicatedin diseases and disorders involving uncontrolled breakdown of connectivetissue. Exemplary diseases and disorders (pathological conditions)include, for example, rheumatoid arthritis, osteoarthritis, septicarthritis, corneal, epidermal or gastric ulceration, snake bite, tumormetastasis, growth, invasion or angiogenesis, periodontal disease,proteinuria, Alzheimer's Disease, multiple sclerosis, coronarythrombosis and bone disease. Also contemplated are the provision ofprocesses for preparing such compositions; the provision of processesfor treating pathological conditions associated with abnormal matrixmetalloprotease activity. A contemplated process effective for treatingsuch pathological conditions acts by selective inhibition ofmetalloproteases associated with such conditions with minimal sideeffects resulting from inhibition of other proteases whose activity isnecessary or desirable for normal body function.

Briefly, therefore, the present invention is directed to a compound ofFormula I or a pharmaceutically acceptable acid or base addition salt ofa compound of Formula I, as well as a pharmaceutical composition of acompound of Formula I or a pharmaceutically acceptable acid or baseaddition salt of a compound of Formula I, and also a process fortreating conditions associated with pathological matrix metalloproteaseactivity comprising administering a matrix metalloprotease inhibitor inan effective dosage to a host suffering from such condition.

The present invention relates to a compound of Formula I:

wherein:

n is an integer zero, 1 or 2;

W is independently selected from the group consisting of —NR⁵COR⁶,—NR⁵S(O)_(z)R⁷ where z is zero, 1, or 2, —NR⁵COOR⁸, —NR⁵CONR⁸R⁹ and—NR¹¹R¹²;

R¹ is cycloalkylene, arylene or heteroarylene;

R² is selected from the group consisting of a hydrogen (hydrido), alkyl,aralkyl, heteroaralkyl, cycloalkylalkyl, heterocycloalkylalkyl,alkoxyalkyl, alkylthioalkyl, hydroxycarbonylalkyl, aroylalkyl, andheteroaroylalkyl group, —(CH₂)x—NR¹¹R¹², or —(CH₂)x—C(O)NR¹¹R¹², whereinx is an integer from zero to 6;

R³ is selected from the group consisting of a hydrogen (hydrido), alkyl,aryl, aralkyl, thioalkyl, heteroaralkyl, heteroaryl, alkoxyalkoxyalkyl,trifluoromethylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl,hydroxycarbonylalkyl, alkoxyalkyl, heterocycloalkylalkyl, aryloxyalkyl,alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl group, or a sulfoxideor sulfone of any of said thio-containing groups, a —(CH₂)x—C(O)NR¹¹R¹²group, wherein x is an integer from zero to 6, and a —(CH₂)y—W group,wherein y is an integer from 1 to 6 and W is defined above;

or R² and R³ together with the atom chain to which they are attachedform a 3-8 membered ring;

R⁴ is a hydrogen (hydrido) or C₁-C₄ alkyl group;

R⁵ is a hydrogen (hydrido) or C₁-C₄ alkyl group;

R⁶ is selected from the group consisting of a hydrogen (hydrido),cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkylgroup, and a —(CH₂)x—NR¹¹R¹² group wherein x is an integer from zero to6. The aryl or heteroaryl groups of R⁶ are optionally substituted(unsubstituted or substituted) with one or more substituentsindependently selected from the group consisting of a halo, C₁-C₄ alkyl,C₁-C₄ alkoxy, nitro, cyano, hydroxy, carboxy, hydroxycarbonylalkyl,—(CH₂)x—NR¹¹R¹², wherein x is an integer from zero to 6,trifluoromethyl, alkoxycarbonyl, aminocarbonyl, thio, alkylsulfonyl,carbonylamino, aminosulfonyl, alkylsulfonamino, alkoxyalkyl,cycolalkyloxy, alkylthioalkyl or alkylthio;

a) or R⁵ and R⁶ together with the atom chain to which they are bondedform a 5- to 7-membered a cyclic amide or imide that is substituted orunsubstituted;

b) or R⁵ and R⁷ together with the atom chain to which they are bondedform a 5- to 7-membered a cyclic sulfonamide that is substituted orunsubstituted;

R⁷ is selected from the group consisting of R⁶ and alkyl;

R⁸ and R⁹ are independently selected from the group consisting of R⁶ andalkyl, or R⁸ and R⁹ together with the depicted nitrogen atom form a 5-to 7-membered ring containing zero or one heteroatom that is oxygen,nitrogen or sulfur;

R¹¹ and R¹² are independently selected from the group consisting of ahydrogen (hydrido), alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, alkanoyl, aralkanoyl, and heteroaralkanoyl group, or R¹¹ andR¹² taken together form a 5 to 8-membered heterocyclo or heteroarylring; and

R¹³ is a hydrogen (hydrido) or C₁-C₆ alkyl group.

The present invention also relates to a compound of Formula II:

wherein:

m is an integer from 1 to 6;

W, R¹, R² and R¹³ have the meanings described above;

R⁴ is a hydrogen (hydrido) or C₁-C₄ alkyl group, as before;

or R⁴ and W of —(CH₂)x—W together with the atom chain to which they areattached form a 4-8-membered ring.

Another particular embodiment of the invention relates to a compound ofFormula III:

wherein R², R³, R⁴, R⁶ and R¹³ are as described above.

One particular embodiment of the invention relates to a compound ofFormula IV:

wherein R², R³, R⁴, R⁸ and R¹³ are as defined previously.

A further particular embodiment of the invention relates to a compoundof Formula V:

wherein R², R³, R⁴, R⁷ and R¹³ are as defined previously.

Yet another particular embodiment of the invention relates to a compoundof Formula VI:

wherein R², R³, R⁴, R⁸, R⁹ and R¹³ are as defined previously.

A still further particular embodiment of the invention relates to acompound of Formula VII:

wherein:

n, W, R¹, R², R³, R⁴ and R¹³ are as defined previously, and

R¹⁴ is selected from the group consisting of a hydrido, C₁-C₆ alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkanoyl,cycloalkylcarbonyl, aralkanoyl, aroyl, and heterocyclylcarbonyl group.R¹⁴ is preferably a hydrido group, in which case a compound of formulaVII becomes a compound of formula I, or an acyl group such as analkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, andheterocyclylcarbonyl group.

A contemplated compound contains an asymmetric carbon atom at thealpha-position so that enantiomeric, d and 1 or R and S, forms of eachcompound exist. A particularly preferred stereoconfiguration for acontemplated enantiomeric compound is shown generically below inFormulas IA and VIIA, wherein R³ is hydrido and not depicted, and W, n,the depicted R groups are as defined before.

In the above formulas, the dashed line represents a bond that extendsbeneath the plane of the page, whereas the solid wedge-shaped linerepresents a bond that extends above the plane of the page, as is usualin stereochemical depictions.

As utilized herein, the term “alkyl”, alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 toabout 12, preferably from 1 to about 10, carbon atoms. Examples of suchradicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Theterm “alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radial having one or more double bonds andcontaining from 2 to about 12 carbon atoms preferably from 2 to about 10carbon atoms. Examples of suitable alkenyl radicals include ethenyl(vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl,1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. The term“alkynyl”, alone or in combination, means a straight-chain hydrocarbonradical having one or more triple bonds and containing from 2 to about12 carbon atoms preferably from 2 to about 10 carbon atoms. Examples ofalkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl,1-butynyl, 2-butynyl, 3-butynyl, and the like.

The term “carbonyl”, alone or in combination, means a —C(═O)— groupwherein the remaining two bonds (valences) can be independentlysubstituted. The term “thiol” or “sulfhydryl”, alone or in combination,means a —SH group. The term “thio” or “thial”, alone or in combination,means a thiaether group; i.e., an ether group wherein the ether oxygenis replaced by a sulfur atom.

The term “amino”, alone or in combination, means an amine or —NH₂ groupwhereas the term mono-substituted amino, alone or in combination, meansa substituted amine —N(H)(substituent) group wherein one hydrogen atomis replaced with a substituent, and disubstituted amine means a—N(substituent)₂ wherein two hydrogen atoms of the amino group arereplaced with independently selected substituent groups. Amines, aminogroups and amides are classes that can be designated as primary (I°),secondary (II°) or tertiary (III°) or unsubstituted, mono-substituted ordi-substituted depending on the degree of substitution of the aminonitrogen. Quaternary amine (IV°) means a nitrogen with four substituents(—N+(substituent)₄) that is positively charged and accompanied by acounter ion or N-oxide means one substituent is oxygen and the group isrepresented as (—N⁺(substituent)₃—O⁻), i.e., the charges are internallycompensated.

The term “cyano”, alone or in combination, means a —C-triple bond—N(—CN) group. The term “azido”, alone or in combination, means a—N-double bond-N-double bond-N (—N═N═N) group.

The term “hydroxyl”, alone or in combination, means a —OH group. Theterm “nitro”, alone or in combination, means a —NO₂ group.

The term “azo”, alone or in combination, means a —N═N— group wherein thebonds at the terminal positions are independently substituted. The term“hydrazino”, alone or in combination, means a —NH—NH— group wherein theremaining two bonds (valences) are independently substituted. Thehydrogen atoms of the hydrazino group can be replaced, independently,with substituents and the nitrogen atoms can form acid addition salts orbe quaternized.

The term “sulfonyl”, alone or in combination, means a —S(═O)₂— groupwherein the remaining two bonds (valences) can be independentlysubstituted. The term “sulfoxido”, alone or in combination, means a—S(═O)₁— group wherein the remaining two bonds (valences) can beindependently substituted. The term “sulfonylamide”, alone or incombination, means a —S(═O)₂—N═ group wherein the remaining three bonds(valences) can be independently substituted. The term “sulfinamido”,alone or in combination, means a —S(═O)₁N═ group wherein the remainingthree bonds (valences) can be independently substituted. The term“sulfenamide”, alone or in combination, means a —S—N═ group wherein theremaining three bonds (valences) can be independently substituted.

The term “alkoxy”, alone or in combination, means an alkyl ether radicalwherein the term alkyl is as defined above. Examples of suitable alkylether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like. The term “cycloalkyl”,alone or in combination, means an alkyl radical which contains fromabout 3 to about 8 carbon atoms and in cyclic. The term“cycloalkylalkyl”, means an alkyl radical as defined above which issubstituted by a cycloalkyl radical containing from about 3 to about 8,preferably from about 3 to about 6, carbon atoms. Examples of suchcycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

The term “aryl”, alone or in combination, means a phenyl, indenyl ornaphthyl radical that optionally carries one or more substituentsselected from alkyl, alkoxy, halogen, hydroxy, amino, nitro and thelike, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl,and the like. The term “aralkyl”, alone or in combination, means analkyl radical as defined above in which one hydrogen atom is replaced byan aryl radical as defined above, such as benzyl, 2-phenylethyl and thelike. The term “aralkoxycarbonyl”, alone or in combination, means aradical of the formula —C(O)—O-aralkyl in which the term “aralkyl” hasthe significance given above. An example of an aralkoxycarbonyl radicalis benzyloxycarbonyl. The term “aryloxy” means a radical of the formulaaryl-O— in which the term aryl has the significance given above. Theterm “aromatic ring” in combinations such as substituted-aromatic ringsulfonamide, substituted-aromatic ring sulfinamide orsubstituted-aromatic ring sulfenamide means aryl or heteroaryl asdefined above.

The terms “alkanoyl” or “alkylcarbonyl”, alone or in combination, meansan acyl radical derived from an alkylcarboxylic acid, examples of whichinclude acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and thelike. The term “cycloalkylcarbonyl” means an acyl group derived from amonocyclic or bridged cycloalkylcarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkylcarboxylic acid which isoptionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The terms “aralkanoyl” or“aralkylcarbonyl” mean an acyl radical derived from an aryl-substitutedalkylcarboxylic acid such as phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyland the like.

The terms “aroyl” or “arylcarbonyl” means an acyl radical derived froman aromatic carboxylic acid. Examples of such radicals include aromaticcarboxylic acids, an optionally substituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl,6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,3-(benzyloxyformamido)-2-naphthoyl, and the like.

The heterocyclyl (heterocyclo) or heterocycloalkyl portion of aheterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkoxycarbonyl, or heterocyclyalkyl group or the like is asaturated or partially unsaturated monocyclic, bicyclic or tricyclicheterocycle that contains one or more hetero atoms selected fromnitrogen, oxygen and sulphur, which is optionally substituted on one ormore carbon atoms by a halogen, alkyl, alkoxy, oxo group , and the like,and/or on a secondary nitrogen atom (i.e., —NH—) by an alkyl,aralkoxycarbonyl, alkanoyl, aryl or arylalkyl or on a tertiary nitrogenatom (i.e. ═N—) by oxido and which is attached via a carbon atom. Thetertiary nitrogen atom with three substituents can also form a N-oxide(═N(O)—) group. The heteroaryl portion of a heteroaroyl,heteroaryloxycarbonyl, or a heteroaralkoxy carbonyl group or the like isan aromatic monocyclic, bicyclic, or tricyclic heterocycle that containsthe hetero atoms and is optionally substituted as defined above withrespect to the definition of heterocyclyl. Examples of such heterocyclyland heteroaryl groups are pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol 4-yl,1-benzyloxycarbonyl-imidazol-4-yl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, oxazolyl,oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl,quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl),isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl),tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl),1,2,3,4-tetrahydroisoquinolinyl (e.g.,1,2,3,4-tetrahydro-1-oxo-isoquinolinyl), quinoxalinyl, 9-carbolinyl,2-benzofurancarbonyl, benzothiophenyl, 1-,2-,4-or 5-benzimidazolyl, andthe like.

The term “cycloalkylalkoxycarbonyl” means an acyl group derived from acycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O—COOHwherein cycloalkylalkyl has the significance given above. The term“aryloxyalkanoyl” means an acyl radical of the formula aryl-O-alkanoylwherein aryl and alkanoyl have the significance given above. The term“heterocyclyloxycarbonyl” means an acyl group derived fromheterocyclyl-O—COOH wherein heterocyclyl is as defined above. The term“heterocyclylalkanoyl” is an acyl radical derived from aheterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl hasthe significance given above. The term “heterocyclylalkoxycarbonyl”means an acyl radical derived from a heterocyclyl-substitutedalkane-O—COOH wherein heterocyclyl has the significance given above. Theterm “heteroaryloxycarbonyl” means an acyl radical derived from acarboxylic acid represented by heteroaryl-O—COOH wherein heteroaryl hasthe significance given above.

The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl (carbamoyl) group derived from anamino-substituted carboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from hydrogen, and alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl radicals and the like. The term “aminoalkanoyl”, meansan acyl group derived from an amino-substituted alkanecarboxylic acidwherein the amino group can be a primary, secondary or tertiary aminogroup containing substituents independently selected from hydrogen,alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.

The term “halogen” means fluorine, chlorine, bromine or iodine. The term“haloalkyll” means an alkyl radical having the significance as definedabove wherein one or more hydrogens are replaced with a halogen.Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl andthe like. The term perfluoroalkyl means an alkyl group wherein eachhydrogen has been replaced by a fluorine atom. Examples of suchperfluoroalkyl groups, in addition to trifluoromethyl above, areperfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the present invention, it has been discovered thatcertain novel substituted-aromatic sulfonamide hydroxamic acid compoundsare effective for inhibition of matrix metalloproteases (“MMPs”)believed to be associated with uncontrolled or otherwise pathologicalbreakdown of connective tissue. In particular, it has been found thatthese substituted-aromatic ring sulfonamide hydroxamic acid,substituted-aromatic ring sulfinamide hydroxamic acid orsubstituted-aromatic ring sulfenamide hydroxamic acid compounds areeffective for inhibition of collagenase Type III (MMP-13), which isbelieved to be particularly destructive to tissue if present orgenerated in abnormal quantities or concentrations. Moreover, it hasbeen discovered that many of these novel sulfur-nitrogen bondedcompounds are selective in the inhibition of MMP-13 and/or other MMPsassociated with diseased conditions without excessive inhibition ofthose collagenases essential to normal bodily function such as tissueturnover and repair or other zinc proteases. More particularly, it hasbeen found that many of the substituted-aryl- orsubstituted-heteroaryl-sulfonamide hydroxamic acids of the invention areselective for MMP-13 with limited or minimal effect on MMP-1.

Set forth in Table 1 to Table 8 inclusive and in Example 1 to Example 15inclusive are several series of preferred classes of compounds.

TABLE 1

Example R₂ R₃ R₄  4

 5

 6

 7

 8

 9

—CH₃

10

—CH₃

11

—CH₃

12

13

14

15

—CH₃

16

17

TABLE 2

Example R₂ R₃ R₄ 18

19

20

21

22

23

—CH₃

24

—CH₃

25

—CH₃

26

27

28

29

—CH₃

30

31

TABLE 3

Example R₂ R₃ R₄ 32

33

—CH₃ 34

35

36

37

—CH₃

38

—CH₃

39

—CH₃

40

41

—CH₃ 42

43

—CH₃

44

45

—CH₃

TABLE 4

Example R₂ R₃ R₄ 46

47

48

49

50

—NH₂ 51

—CH₃

52

—CH₃

53

—CH₃

54

55

56

57

—CH₃

58

59

TABLE 5

Example R₂ R₃ R₄  4

—CH₃

 5

 6

 7

 8

—CH₃

 9

 10

 11

 12 —CH₃ —CH₃

 13 —CH₃

 14 —CH₃

 15 —CH₃

 16

—CH₃

 17

 18

 19

 20

—CH₃

 21

 22

 23

 24

—CH₃

 25

 26

 27

 28

—CH₃

 29

 30

 31

 32 —CH₃ —CH₃

 33 —CH₃

 34 —CH₃

 35 —CH₃

 36

—CH₃

 37

 38

 39

 40

—CH₃

 41

 42

 43

 44

—CH₃

 45

 46

 47

 48

—CH₃

 49

 50

 51

 52 —CH₃ —CH₃

 53 —CH₃

 54 —CH₃

 55 —CH₃

 56

—CH₃

 57

 58

 59

 60

—CH₃

 61

 62

 63

 64

—CH₃

 65

 66

 67

 68

—CH₃

 69

 70

 71

 72 —CH₃ —CH₃

 73 —CH₃

 74 —CH₃

 75 —CH₃

 76

—CH₃

 77

 78

 79

 80

—CH₃

 81

 82

 83

 84

—CH₃

 85

 86

 87

 88

—CH₃

 89

 90

 91

 92 —CH₃ —CH₃

 93 —CH₃

 94 —CH₃

 95 —CH₃

 96

—CH₃

 97

 98

 99

100

—CH₃

101

102

103

104

—CH₃

105

106

107

108

—CH₃

109

110

111

112 —CH₃ —CH₃

113 —CH₃

114 —CH₃

115 —CH₃

116

—CH₃

117

118

119

120

—CH₃

121

122

123

124

—CH₃

125

126

127

128

—CH₃

129

130

131

132 —CH₃ —CH₃

133 —CH₃

134 —CH₃

135 —CH₃

136

—CH₃

137

138

139

140

—CH₃

141

142

143

144

—CH₃

145

146

147

148

—CH₃

149

150

151

152 —CH₃ —CH₃

153 —CH₃

154 —CH₃

155 —CH₃

156

—CH₃

157

158

159

160

—CH₃

161

162

163

164

—CH₃

165

166

167

168

—CH₃

169

170

171

172 —CH₃ —CH₃

173 —CH₃

174 —CH₃

175 —CH₃

176

—CH₃

177

178

179

180

—CH₃

181

182

183

184

—CH₃

185

186

187

188

—CH₃

189

190

191

192 —CH₃ —CH₃

193 —CH₃

194 —CH₃

195 —CH₃

196

—CH₃

197

198

199

200

—CH₃

201

202

203

204

—CH₃

205

206

207

208

—CH₃

209

210

211

212 —CH₃ —CH₃

213 —CH₃

214 —CH₃

215 —CH₃

216

—CH₃

217

218

219

220

—CH₃

221

222

223

224

—CH₃

225

226

227

228

—CH₃

229

230

231

232 —CH₃ —CH₃

233 —CH₃

234 —CH₃

235 —CH₃

236

—CH₃

237

238

239

240

—CH₃

241

242

243

244

—CH₃

245

246

247

248

—CH₃

249

250

251

252 —CH₃ —CH₃

253 —CH₃

254 —CH₃

255 —CH₃

256

—CH₃

257

258

259

260

—CH₃

261

262

263

264

—CH₃

265

266

267

268

—CH₃

269

270

271

272 —CH₃ —CH₃

273 —CH₃

274 —CH₃

275 —CH₃

276

—CH₃

277

278

279

280

—CH₃

281

282

283

284

—CH₃

285

286

287

288

—CH₃

289

290

291

292 —CH₃ —CH₃

293 —CH₃

294 —CH₃

295 —CH₃

296

—CH₃

297

298

299

300

—CH₃

301

302

303

TABLE 6

Example R² R³ R⁴ 304

—CH₃

305

306

307

308

—CH₃

309

310

311

312 —CH₃ —CH₃

313 —CH₃

314 —CH₃

315 —CH₃

316

—CH₃

317

318

319

320

—CH₃

321

322

323

324

—CH₃

325

326

327

328

—CH₃

329

330

331

332 —CH₃ —CH₃

333 —CH₃

334 —CH₃

335 —CH₃

336

—CH₃

337

338

339

340

—CH₃

341

342

343

344

—CH₃

345

346

347

348

—CH₃

349

350

351

352 —CH₃ —CH₃

353 —CH₃

354 —CH₃

355 —CH₃

356

—CH₃

357

358

359

360

—CH₃

361

362

363

364

—CH₃

365

366

367

368

—CH₃

369

370

371

372 —CH₃ —CH₃

373 —CH₃

374 —CH₃

375 —CH₃

376

—CH₃

377

378

379

380

—CH₃

381

382

383

384

—CH₃

385

386

387

388

—CH₃

389

390

391

392 —CH₃ —CH₃

393 —CH₃

394 —CH₃

395 —CH₃

396

—CH₃

397

398

399

400

—CH₃

401

402

403

404

—CH₃

405

406

407

408

—CH₃

409

410

411

412 —CH₃ —CH₃

413 —CH₃

414 —CH₃

415 —CH₃

416

—CH₃

417

418

419

420

—CH₃

421

422

423

424

—CH₃

425

426

427

428

—CH₃

429

430

431

432 —CH₃ —CH₃

433 —CH₃

434 —CH₃

435 —CH₃

436

—CH₃

437

438

439

440

—CH₃

441

442

443

444

—CH₃

445

446

447

448

—CH₃

449

450

451

452 —CH₃ —CH₃

453 —CH₃

454 —CH₃

455 —CH₃

456

—CH₃

457

458

459

460

—CH₃

461

462

463

464

—CH₃

465

466

467

468

—CH₃

469

470

471

472 —CH₃ —CH₃

473 —CH₃

474 —CH₃

475 —CH₃

476

—CH₃

477

478

479

480

—CH₃

481

482

483

484

—CH₃

485

486

487

488

—CH₃

489

490

491

492 —CH₃ —CH₃

493 —CH₃

494 —CH₃

495 —CH₃

496

—CH₃

497

498

499

500

—CH₃

501

502

503

504

—CH₃

505

506

507

508

—CH₃

509

510

511

512 —CH₃ —CH₃

513 —CH₃

514 —CH₃

515 —CH₃

516

—CH₃

517

518

519

520

—CH₃

521

522

523

524

—CH₃

525

526

527

528

—CH₃

529

530

531

532 —CH₃ —CH₃

533 —CH₃

534 —CH₃

535 —CH₃

536

—CH₃

537

538

539

540

—CH₃

541

542

543

544

—CH₃

545

546

547

548

—CH₃

549

550

551

552 —CH₃ —CH₃

553 —CH₃

554 —CH₃

555 —CH₃

556

—CH₃

557

558

559

560

—CH₃

561

562

563

TABLE 7

Example R₂ R³ R⁴ 564

—CH₃

565

566

567

568

—CH₃

569

570

571

572 —CH₃ —CH₃

573 —CH₃

574 —CH₃

575 —CH₃

576

—CH₃

577

578

579 —CH

580

—CH₃

581

582

583

584

—CH₃ —CH₃ 585

—CH₃ 586

—CH₃ 587

—CH₃ 588

—CH₃ —CH₃ 589

—CH₃ 590

—CH₃ 591

—CH₃ 592 —CH₃ —CH₃ —CH₃ 593 —CH₃

—CH₃ 594 —CH₃

—CH₃ 595 —CH₃

—CH₃ 596

—CH₃ —CH₃ 597

—CH₃ 598

—CH₃ 599

—CH₃ 600

—CH₃ —CH₃ 601

—CH₃ 602

—CH₃ 603

—CH₃ 604

—CH₃

605

606

607

608

—CH₃

609

610

611

612 —CH₃ —CH₃

613 —CH₃

614 —CH₃

615 —CH₃

616

—CH₃

617

618

619

620

—CH₃

621

622

623

624

—CH₃

625

626

627

628

—CH₃

629

630

631

632 —CH₃ —CH₃

633 —CH₃

634 —CH₃

635 —CH₃

636

—CH₃

637

638

639

640

—CH₃

641

642

643

644

—CH₃

645

646

647

648

—CH₃

649

650

651

652 —CH₃ —CH₃

653 —CH₃

654 —CH₃

655 —CH₃

656

—CH₃

657

658

659

660

—CH₃

661

662

663

664

—CH₃

665

666

667

668

—CH₃

669

670

671

672 —CH₃ —CH₃

673 —CH₃

674 —CH₃

675 —CH₃

676

—CH₃

677

678

679

680

—CH₃

681

682

683

684

—CH₃

685

686

687

688

—CH₃

689

690

691

692 —CH₃ —CH₃

693 —CH₃

694 —CH₃

695 —CH₃

696

—CH₃

697

698

699

700

—CH₃

701

702

703

704

—CH₃

705

706

707

708

—CH₃

709

710

711

712 —CH₃ —CH₃

713 —CH₃

714 —CH₃

715 —CH₃

716

—CH₃

717

718

719

720

—CH₃

721

722

723

724

—CH₃

725

726

727

728

—CH₃

729

730

731

732 —CH₃ —CH₃

733 —CH₃

734 —CH₃

735 —CH₃

736

—CH₃

737

738

739

740

—CH₃

741

742

743

744

—CH₃

745

746

747

748

—CH₃

749

750

751

752 —CH₃ —CH₃

753 —CH₃

754 —CH₃

755 —CH₃

756

—CH₃

757

758

759

760

—CH₃

761

762

763

TABLE 8

Example R² R³ R⁴ 764

—CH₃

765

766

767

768

—CH₃

769

770

771

772 —CH₃ —CH₃

773 —CH₃

774 —CH₃

775 —CH₃

776

—CH₃

777

778

779

780

—CH₃

781

782

783

784

—CH₃

785

786

787

788

—CH₃

789

790

791

792 —CH₃ —CH₃

793 —CH₃

794 —CH₃

795 —CH₃

796

—CH₃

797

798

799

800

—CH₃

801

802

803

804

—CH₃

805

806

807

808

—CH₃

809

810

811

812 —CH₃ —CH₃

813 —CH₃

814 —CH₃

815 —CH₃

816

—CH₃

817

818

819

820

—CH₃

821

822

823

824

—CH₃

825

826

827

828

—CH₃

829

830

831

832 —CH₃ —CH₃

833 —CH₃

834 —CH₃

835 —CH₃

836

—CH₃

837

838

839

840

—CH₃

841

842

843

844

—CH₃ —NH₂ 845

—NH₂ 846

—NH₂ 847

—NH₂ 848

—CH₃ —NH₂ 849

—NH₂ 850

—NH₂ 851

—NH₂ 852 —CH₃ —CH₃ —NH₂ 853 —CH₃

—NH₂ 854 —CH₃

—NH₂ 855 —CH₃

—NH₂ 856

—CH₃ —NH₂ 857

—NH₂ 858

—NH₂ 859

—NH₂ 860

—CH₃ —NH₂ 861

—NH₂ 862

—NH₂ 863

—NH₂ 864

—CH₃

865

866

867

868

—CH₃

869

870

871

872 —CH₃ —CH₃

873 —CH₃

874 —CH₃

875 —CH₃

876

—CH₃

877

878

879

880

—CH₃

881

882

883

884

—CH₃

885

886

887

888

—CH₃

889

890

891

892 —CH₃ —CH₃

893 —CH₃

894 —CH₃

895 —CH₃

896

—CH₃

897

898

899

900

—CH₃

901

902

903

904

—CH₃

905

906

907

908

—CH₃

909

910

911

912 —CH₃ —CH₃

913 —CH₃

914 —CH₃

915 —CH₃

916

—CH₃

917

918

919

920

—CH₃

921

922

923

924

—CH₃

925

926

927

928

—CH₃

929

930

931

932 —CH₃ —CH₃

933 —CH₃

934 —CH₃

935 —CH₃

936

—CH₃

937

938

939

940

—CH₃

941

942

943

944

—CH₃

945

946

947

948

—CH₃

949

950

951

952 —CH₃ —CH₃

953 —CH₃

954 —CH₃

955 —CH₃

956

—CH₃

957

958

959

960

—CH₃

961

962

963

964

—CH₃

965

966

967

968

—CH₃

969

970

971

972 —CH₃ —CH₃

973 —CH₃

974 —CH₃

975 —CH₃

976

—CH₃

977

978

979

980

—CH₃

981

982

983

984

—CH₃

985

986

987

988

—CH₃

989

990

991

992 —CH₃ —CH₃

993 —CH₃

994 —CH₃

995 —CH₃

996

—CH₃

997

998

999

1000

—CH₃

1001

1002

1003

1004

—CH₃

1005

1006

1007

1008

—CH₃

1009

1010

1011

1012 —CH₃ —CH₃

1013 —CH₃

1014 —CH₃

1015 —CH₃

1016

—CH₃

1017

1018

1019

1020

—CH₃

1021

1022

1023

1024

—CH₃

1025

1026

1027

1028

—CH₃

1029

1030

1031

1032 —CH₃ —CH₃

1033 —CH₃

1034 —CH₃

1035 —CH₃

1036

—CH₃

1037

1038

1039

1040

—CH₃

1041

1042

1043

Treatment Process

A process for treating a host mammal having a condition associated withpathological matrix metalloprotease activity is also contemplated. Thatprocess comprises administering a metalloprotease inhibitor describedhereinbefore in an MMP enzyme-inhibiting effective amount to a mammalianhost having such a condition. The use of administration repeated aplurality of times is particularly contemplated.

A contemplated inhibitor compound is used for treating a host mammalsuch as a mouse, rat, rabbit, dog, horse, primate such as a monkey,chimpanzee or human that has a condition associated with pathologicalmatrix metalloprotease activity.

Also contemplated is the similar use of a contemplated metalloproteaseinhibitor compound in the treatment of a disease state that can beaffected by the activity of metalloproteases such as TNF-α convertase.Exemplary of such disease states are the acute phase responses of shockand sepsis, coagulation responses, hemorrhage and cardiovasculareffects, fever and inflammation, anorexia and cachexia.

In treating a disease condition associated with pathological matrixmetalloproteinase activity, a contemplated MMP inhibitor compound can beused, where appropriate, in the form of an amine salt derived from aninorganic or organic acid. Exemplary acid salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate.

Also, a basic nitrogen-containing group can be quaternized with suchagents as lower alkyl (C₁-C₆) halides, such as methyl, ethyl, propyl,and butyl chloride, bromides, and iodides; dialkyl sulfates likedimethyl, diethyl, dibuytl, and diamyl sulfates, long chain (C₈-C₂₀)halides such as decyl, lauryl, myristyl and dodecyl chlorides, bromidesand iodides, aralkyl halides like benzyl and phenethyl bromides, andothers to provide enhanced water-solubility. Water or oil-soluble ordispersible products are thereby obtained as desired. The salts areformed by combining the basic compounds with the desired acid.

Other compounds useful in this invention that are acids can also formsalts. Examples include salts with alkali metals or alkaline earthmetals, such as sodium, potassium, calcium or magnesium or with organicbases or basic quaternary ammonium salts.

In some cases, the salts can also be used as an aid in the isolation,purification or resolution of the compounds of this invention.

Total daily dose administered to a host mammal in single or divideddoses of an MMP enzyme-inhibiting effective amount can be in amounts,for example, of about 0.001 to about 30 mg/kg body weight daily and moreusually about 0.01 to about 10 mg. Dosage unit compositions can containsuch amounts or submultiples thereof to make up the daily dose. Asuitable dose can be administered, in multiple sub-doses per day.Multiple doses per day can also increase the total daily dose, shouldsuch dosing be desired by the person prescribing the drug.

The dosage regimen for treating a disease condition with a compoundand/or composition of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed can vary widely and thereforecan deviate from the preferred dosage regimen set forth above.

A compound useful in the present invention can be formulated as apharmaceutical composition. Such a composition can then be administeredorally, parenterally, by inhalation spray, rectally, or topically indosage unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants, and vehicles asdesired. Topical administration can also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. Formulation of drugs is discussed in, for example, Hoover,John E., Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds.,Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables. Dimethyl acetamide, surfactantsincluding ionic and non-ionic detergents, polyethylene glycols can beused. Mixtures of solvents and wetting agents such as those discussedabove are also useful.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter, synthetic mono- di- or triglycerides, fatty acids andpolyethylene glycols that are sold at ordinary temperatures but liquidat the rectal temperature and will therefore melt in the rectum andrelease the drug.

Solid dosage forms for oral administration can include capsules,tablets, pills, powders, and granules. In such solid dosage forms, thecompounds of this invention are ordinarily combined with one or moreadjuvants appropriate to the indicated route of administration. Ifadministered per os, the compounds can be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets can contain a controlled-release formulation as canbe provided in a dispersion of active compound in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage formscan also comprise buffering agents such as sodium citrate, magnesium orcalcium carbonate or bicarbonate. Tablets and pills can additionally beprepared with enteric coatings.

For therapeutic purposes, formulations for parenteral administration canbe in the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions can beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. The compounds can be dissolved in water, polyethyleneglycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The amount of active ingredient that can be combined with the carriermaterials to produce a single dosage form varies depending upon themammalian host treated and the particular mode of administration.

Certain of the sulfonamide, sulfinamide or sulfenamide, compounds ofthis invention that are administered in accordance with anabove-discussed process can serve as prodrugs to other compounds of thisinvention. Prodrugs are drugs that can be chemically converted in vivoor in vitro by biological systems into an active derivative orderivatives. Prodrugs are administered in essentially the same manner asthe other pharmaceutical compounds of the invention. Exemplary prodrugscorrespond in structure to a compound of formula VII in which R¹⁴ isacyl.

Preparation of Useful Compounds

Expressly included among the individual compounds of the presentinvention are carboxylic acid compounds corresponding to each of thehydroxamic acid compounds of Tables 1-8. Each such carboxylic acidcompound has the structure depicted for the corresponding hydroxamicacid compound of the tables, except that the carboxylic acid contains an—OH group in the same location in the structure as the HO—NH-group ofthe hydroxamic acid. Thus, the invention specifically includes acarboxylic acid compound corresponding to each of: Examples 4-17 ofTable 1; Examples 18-31 of Table 2; Examples 32-45 of Table 3; Examples46-59 of Table 4; Examples 4-303 of Table 5; Examples 304-563 of Table6; Examples 564-763 of Table 7; and Examples 764-1043 of Table 8. Theinvention also specifically includes the carboxylic acid compoundscorresponding to each of working Examples 1-4 that are providedhereinafter.

Schemes I and III and Schemes 1, 2, 4, 5, 6, and 7 illustrate procedureswith examples of chemical transformations that may be useful for thepreparation of compounds of this invention. These syntheses, as with allof the reactions discussed herein, can be carried out under a dry inertatmosphere such a nitrogen or argon if desired. Selected reactions knownto those skilled in the art, can be carried out under a dry atmospheresuch as dry air whereas other synthetic steps, for example, aqueous acidor base ester or amide hydrolyses, can be carried out under laboratoryair.

Thus, in general, the choices of starting material and reactionconditions can vary as is well know to those skilled in the art.Usually, no single set of conditions is limiting since variations can beapplied as required. Conditions will also will be selected as desired tosuit a specific purpose such as small scale preparations or large scalepreparations. In either case, the use of less safe or lessenvironmentally sound materials or reagents will usually be minimized.Examples of such less desirable materials are diazomethane, diethylether, heavy metal salts, dimethyl sulfide, chloroform, benzene and thelike.

Scheme 1 shows the conversion of an N-substituted alpha-amino acid,protected or unprotected, into a compound of Formula I. The amino acidmay be protected with a group P such as an alkyl ester such as methyl,ethyl, tert-butyl, tetrahydropyranyl and the like or arylalkyl estersuch as benzyl. Treatment of this amine with a sulfonyl, sulfinyl orsulfenyl chloride would provide the corresponding amide. A base wouldnormally be used to inactivate the HCl released from the acid chlorideand it would be such that it would not react with the sulfonyl chloride,i.e., ammonia, I° or II° amines would not normally be used. Examples ofbases that can be used include, for example, metal hydroxides such assodium, potassium, lithium or magnesium hydroxide, oxides such as thoseof sodium, potassium, lithium, calcium or magnesium, metal carbonatessuch as those of sodium, potassium, lithium, calcium or magnesium, metalbicarbonates such as sodium bicarbonate or potassium bicarbonate, I°,II° or III° organic amines such as alkyl amines, arylalkyl amines,alkylarylalkyl amines, heterocyclic amines or heteroaryl amines,ammonium hydroxides or quaternary ammonium hydroxides. As non-limitingexamples, such amines can include triethyl amine, trimethyl amine,diisopropyl amine, methyldiisopropyl amine, diazabicyclononane,tribenzyl amine, dimethylbenzyl amine, morpholine, N-methylmorpholine,N,N′-dimethylpiperazine, N-ethylpiperidine,1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine,quinoline, tetramethylethylenediamine and the like. Non-limitingexamples of ammonium hydroxides, usually made from amines and water, caninclude ammonium hydroxide, triethyl ammonium hydroxide, trimethylammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzylammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholiniumhydroxide, N-methylmorpholinium hydroxide, N,N′-dimethylpiperaziniumhydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limitingexamples, quaternary ammonium hydroxides can include tetraethyl ammoniumhydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammoniumhydroxide, benzymethyldiisopropyl ammonium hydroxide,methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammoniumhydroxide, N,N-dimethylmorpholinium hydroxide,N,N,N′,N′-tetramethylpiperazenium hydroxide, andN-ethyl-N′-hexylpiperidinium hydroxide and the like. Metal hydrides,amide or alcoholates such as calcium hydride, sodium hydride, potassiumhydride, lithium hydride, sodium methoxide, potassium tert-butoxide,calcium ethoxide, magnesium ethoxide, sodium amide, potassiumdiisopropyl amide and the like may also be suitable reagents.Organometallic deprotonating agents such as alkyl or aryl lithiumreagents such as methyl, phenyl or butyl lithium, Grignard reagents suchas methylmagnesium bromide or methymagnesium chloride, organocadiumreagents such as dimethylcadium and the like may also serve as bases forcausing salt formation or catalyzing the reaction. Quaternary ammoniumhydroxides or mixed salts are also useful for aiding phase transfercouplings or serving as phase transfer reagents.

The first reaction in Scheme 1 also illustrated the use of a mixedsolvent THF/H₂O. This is one solvent system however others may be usefulalso. For example, the reaction media can consist of a single solvent,mixed solvents of the same or different classes or serve as a reagent ina single or mixed solvent system. The solvents can be protic, non-proticor dipolar aprotic. Non-limiting examples of protic solvents includewater, methanol (MeOH), denatured or pure 95% or absolute ethanol,isopropanol and the like. Typical non-protic solvents include acetone,tetrahydrofurane (THF), dioxane, diethylether (ether), tert-butylmethylether (TBME), aromatics such as xylene, toluene, or benzene, ethylacetate, methyl acetate, butyl acetate, trichloroethane, methylenechloride, ethylenedichloride (EDC), hexane, heptane, isooctane,cyclohexane and the like. Dipolar aprotic solvents include compoundssuch as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile,nitromethane, tetramethylurea, N-methylpyrrolidone and the like.

Non-limiting examples of ammonium hydroxides, usually made from aminesand water, can include ammonium hydroxide, triethyl ammonium hydroxide,trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide,tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide,morpholinium hydroxide, N-methylmorpholinium hydroxide,N,N′dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, andthe like. As non-limiting examples, quaternary ammonium hydroxides caninclude tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide,dimethyldiiospropyl ammonium hydroxide, benzymethyldiisopropyl ammoniumhydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzylammonium hydroxide, N,N-dimethylmorpholinium hydroxide, N,N,N′,N′,-tetramethylpiperazenium hydroxide, and N-ethyl-N′-hexylpiperidiniumhydroxide and the like. Metal hydrides, amide or alcoholates such ascalcium hydride, sodium hydride, potassium hydride, lithium hydride,sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesiumethoxide, sodium amide, potassium diisopropyl amide and the like mayalso be suitable reabents. Organometallic deprotonating agents such asalkyl or aryl lithium reagents such as methyl, phenyl or butyl lithium,Grignard reagents such as methylmagnesium bromide or methymagnesiumchloride, organocadium reagents such as dimethylcadium and the like mayalso serve as bases for causing salt formation or catalyzing thereaction. Quaternary ammonium hydroxides or mixed salts are also usefulfor aiding phase transfer couplings or serving as phase transferreagents.

The first reaction in Scheme 1 also illustrated the use of a mixedsolvent THF/H₂O. This is one solvent system however others may be usefulalso. For example, the reaction media can consist of a single solvent,mixed solvents of the same or different classes or serve as a reagent ina single or mixed solvent system. The solvents can be protic, non-proticor dipolar aprotic. Non-limiting examples of protic solvents includewater, methanol (MeOH), denatured or pure 95% or absolute ethanol,isopropanol and the like. Typical non-protic solvents include acetone,tetrahydrofurane (THF), dioxane, diethylether (ether), tert-butylmethylether (TBME), aromatics such as xylene, toluene, or benzene, ethylacetate, methyl acetate, butyl acetate, trichloroethane, methylenechloride, ethylenedichloride (EDC), hexane, heptane, isooctane,cyclohexane and the like. Dipolar aprotic solvents include compoundssuch as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile,nitromethane, tetramethylurea, N-methylpyrrolidone and the like.

Non-limiting examples of reagents that can be used as solvents or aspart of a mixed solvent system include organic or inorganic mono- ormulti-protic acids or bases such as hydrochloric acid, phosphoric acid,sulfuric acid, acetic acid, formic acid, citric acid, succinic acid,triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine,piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols,ammonia or amines for making esters or amides and the like.

Acids are used in many reactions during various synthesis. Scheme 1illustrates acid use for the removal of the THP protecting group toproduce the hydroxamic acid of Formula I. The acid might be mono-, di-or tri-protic organic or inorganic acids. Examples of acids includehydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formicacid, citric acid, succinic acid, hydrobromic acid, hydrofluoric acid,carbonic acid, phosphorus acid, p-toluene sulfonic acid,trifluoromethane sulfonic acid, trifluoroacetic acid, difluoroaceticacid, benzoic acid, methane sulfonic acid, benzene sulfonic acid,2,6-dimethylbenzene sulfonic acid, trichloroacetic acid, nitrobenzoicacid, dinitrobenzoic acid, trinitrobenzoic acid, and the like. Theymight also be Lewis acids such as aluminum chloride, borontrifluoride,antimony pentafluoride and the like. A preferred solvent in this typereaction is dioxane eith an alcohol or water however almost any solventsystem with one component being a protic solvent can be useful.

Scheme I illustrates conversion of a carboxylic acid protected as anester or amide into an hydroxamic acid derivative such as aO-arylalkylether or O-cycloalkoxyalkylether group. In particular, thethis Scheme the protecting group on the hydroxylamine is the THP group.In the case where hydroxylamine is used, treatment of an ester or amidewith one or more equivalents of hydroxylamine hydrochloride at roomtemperature or above in a solvent or solvents, usually protic orpartially protic, such as those listed above can provide a hydroxamicacid directly. This exchange process may be further catalyzed by theaddition of additional acid. Alternatively, a base such as a salt of analcohol used as a solvent, for example, sodium methoxide in methanol,can be used to form hydroxylamine from hydroxylamine hydrochloride insitu which can exchange with an ester or amide. As mentioned above,exchange can be carried out with a protected hydroxyl amine such astetrahydropyranyl-hydroxyamine (THPONH₂), benzylhydroxylamine (BnONH₂),and the like in which case compounds such as shown in Scheme 1 that aretetrahydropyranyl (THP) or benzyl (Bn) hydroxamic acid derivatives arethe products. Removal of the protecting groups when desired, forexample, following further transformations in another part of themolecule or following storage, is accomplished by standard methods wellknown in the art such as acid hydrolysis of the THP group as discussedabove or reductive removal of the benzyl group with hydrogen and a metalcatalyst such as palladium, platinum, palladium on carbon or nickel.

In the case where P is hydrogen, i.e., where the intermediate is acarboxylic acid, standard coupling reactions can be used. For example,the acid can be converted into an acid chloride, mixed anhydride oractivated ester and treated with hydroxylamine or a protectedhydroxylamine in the presence of a non-competitive base to the nitrogenacylated compound. This is the same product as discussed above.Couplings of this nature are well known in the art and especially theart related to peptide and amino acid chemistry.

Scheme II illustrates another possible synthesis of the compounds ofFormula I starting with a protected or unprotected amino acid.Sulfonylation of the amino group is accomplished as discussed above toproduce the sulfonamide II-B. This compound is a secondary sulfonamideand, as such, is acidic and can be alkylated with an R² group.Alkylation, a process well known in the art, can be carried by treatmentof the sulfonamide with base to form the corresponding anion, adding anelectrophilic reagent and allowing the SN₂ reaction to proceed.Electrophiles include halogen derivatives, sulfonate esters, epoxidesand the like. The bases and solvents discussed with regard to Scheme Iare applicable in this Scheme. Preferred bases are those that arehindered such that competition with the electrophile is minimized.Additional preferred bases are metal hydrides, amide anions ororganometallic bases such as a butyl lithium. The solvents, solventmixtures or solvent/reagent mixtures discussed are satisfactory butnon-protic or dipolar aprotic solvents such as acetone, acetonitrile,DMF and the like are examples of preferred classes.

Scheme III illustrates the potential for use of a sulfonyl chloridereagent, specifically nitrobenzenesulfonyl chloride, to preparecompounds of this invention. It should be noted that this reagent is forillustration and is not to be considered limiting or required. Aftercoupling with an amino acid and alkylation of the coupling product ifrequired, the nitrosulfonamide can be reduced to provide a useful aminocompound. The amino group can be alkylated if desired. It can also beacylated with an aroyl chloride, heteroaryl or other R⁶ amine carbonylfroming agent to form a —C(═O)— or —S(═O)n— compound of this invention.The amino sulfonamide can also be reacted with a carbonic acid esterchloride as shown in Scheme IV, a sulfonyl chloride as shown in Scheme Vor in Scheme VII or a carbamoyl chloride or isocyanate as shown inScheme VI to produce the corresponding carbamate, sulfonamides, or ureasof this invention. Acylation of amines of this type are well known inthe art and the reagents are also well known. Usually these reactionsare carried out in aprotic solvents under an inert or/and dry atmosphereat about 45° C. to about −10° C. An equivalent of a non-competitive baseis usually used with sulfonyl chloride, acid chloride or carbonylchloride reagents. Following this acylation step, synthesis of thehydroxamic acid products of this invention can proceed as discussedabove for Scheme I and Scheme II.

Schemes II through VI also illustrate the possible reduction of anitrobenzenesulfonamide to produce an amino sulfonamide. The reductionof nitro groups to amines is will know in the art with a preferredmethod being hydrogenation. There is usually a metal catalyst such asRh, Pd, Pt, Ni or the like with or without an additional support such ascarbon, barium carbonate and the like. Solvents can be protic ornon-protic pure solvents or mixed solvents as required. The reductionscan be carried out at atmospheric pressure to a pressure of multipleatmospheres with atmospheric pressure to about 40 pounds per square inch(psi) preferred.

Other sulfonyl chloride reagents can also be used in the preparation ofcompounds of this invention as outline in the Schemes. Examples arefluoroaryl or fluoroheteroaryl sulfonyl chlorides, azidoaryl orazidoheteroaryl or amide, carbonate, carbamate or urea substituted arylor heteroaryl sulfonyl chloride reagents. Azides, for example, can bereduced to an amino group using hydrogen with a metal catalyst or metalchelate catalyst or activated hydride transfer reagent. The fluorosubstituted sulfonic acid or sulfonamide can be treated with anucleophile such as ammonia or a primary amine, under pressure ifdesired, to provide an amino or substituted (R5) amino group that canthen be reacted a reagent as outline in Scheme III and in Schemes 4-7inclusive.

Compounds of the present can possess one or more asymmetric carbon atomsand are thus capable of existing in the form of optical isomers as wellas in the form of racemic or nonracemic mixtures thereof. The opticalisomers can be obtained by resolution of the racemic mixtures accordingto conventional processes well known in the art, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules, e.g., esters, amides, acetals,ketals, and the like, by reacting compounds of Formula I with anoptically active acid in an activated form, a optically active diol oran optically active isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomericaly pure compound. In some cases hydrolysis to the parentoptically active drug is not necessary prior to dosing the patient sincethe compound can behave as a prodrug. The optically active compounds ofFormula I can likewise be obtained by utilizing optically activestarting materials.

Contemplated equivalents of the general formulas set forth above for theMMP inhibitor compounds and derivatives as well as the intermediates arecompounds otherwise corresponding thereto and having the same generalproperties such as tautomers thereof and compounds wherein one or moreof the various R groups are simple variations of the substituents asdefined therein, e.g., wherein R is a higher alkyl group than thatindicated. In addition, where a substituent is designated as, or can be,a hydrogen, the exact chemical nature of a substituent which is otherthan hydrogen at that position, e.g., a hydrocarbyl radical or ahalogen, hydroxy, amino and the like functional group, is not criticalso long as it does not adversely affect the overall activity and/orsynthesis procedure. For example, two hydroxyl groups, two amino groups,two thiol groups or a mixture of two hydrogen-heteroatom groups on thesame carbon are know not to be stable without protection or as aderivative.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

BEST MODE FOR CARRYING OUT THE INVENTION

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limiting ofthe remainder of the disclosure in any way whatsoever.

EXAMPLE 1N-Hydroxy-2(R)-[[(4-benzoylamino)benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanamide,Hydrochloride

Part A: To a stirred solution of D-valine (10.0 g) in a 2:1 mixture ofTHF/water (200 mL) containing 3 equiv. of triethylamine at 5° C. isadded 4-(benzoylamino)benzenesulfonyl chloride (0.9 equiv.) and thereaction is stirred to room temperature overnight. The resulting mixtureis diluted with dichloromethane, and washed with 1N HCl, and water. Theorganic layer is dried over magnesium sulfate, filtered and concentratedin vacuo to provide the desiredN-[(4-benzoylamino)benzenesulfonyl]-(D)-valine as a crude product. Asolution of the crude acid (10 grams) in 80 mL of dry toluene is chargedwith dimethylformamide di-tert-butylacetal (45 mL) and heated to 100° C.for several hours. The resulting cooled solution is concentrated byrotary evaporation and purified by silica gel chromatography to providethe desired N-[(4-benzoylamino)benzenesulfonyl]-(D)-valine, tert-butylester.

Part B: To a dimethylformamide solution (100 mL) of the tert-butyl esterfrom Part A (5.0 grams) is added 4-(2-chloroethyl)-morpholinehydrochloride (1.3 equivalents) and potassium carbonate (3 equivalents);this suspension is heated to 70° C. for five hours. The resultingsuspension is cooled and diluted with water (500 mL) and extracted withethyl acetate. The organic layer is washed with water (2×200 mL),saturated sodium bicarbonate (2×200 mL), and brine, dried over magnesiumsulfate, filtered and concentrated to yield the desired product, t-butyl2(R)-[[(4-benzoylamino)benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoate,which can be purified by silica gel chromatography.

Part C: t-Butyl2(R)-[[(4-benzoylamino)benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoatefrom Part A (4.0 grams) in 100 mL of anhydrous dichloromethane, iscooled to −50° C., and dry HCl gas is bubbled into the reaction flaskfor 20 minutes. The flask is the sealed and allowed to warm to roomtemperature over three to four hours. The solvent is removed by rotaryevaporation and the desired acid, hydrochloride salt,(2(R)-[[(4-benzoylamino)benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoicacid hydrochloride) is triturated with ether hexane and filtered. Thedried precipitate is used without further purification.

Part D:2(R)-[[(4-benzoylamino)benzene-sulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoicacid hydrochloride from Part C (3.8 grams) and 1-hydroxybenzotriazole(1.5 equivalents) are dissolved in anhydrous dimethylformamide (50 mL)and cooled to 10° C. To this is added N-methylmorpholine (3 equivalents)followed by EDC (1.1 equivalents) and this solution is stirred for twohours at 10° C. To this is added O-tetrahydropyranyl (0-THP)hydroxylamine (2 equivalents) and the solution is stirred overnight atroom temperature. The resulting mixture is diluted with 200 mL of waterand extracted with ethyl acetate. The organic layer is washed withsaturated sodium bicarbonate and brine, dried over magnesium sulfate,filtered and concentrated to yield the desired O-THP-protectedhydroxamate,N-tetrahydropyranyloxy-2(R)-[[(4-benzoylamino)-benzenesulfonyl][(4-ethylmorpholino)-amino]-3-methylbutanamide.Further purification by silica gel chromatography provides a mixture ofdesired diastereomers which are combined.

N-tetrahydropyranyloxy-2(R)-[[(4-benzoylamino)-benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanamide(4.0 grams), is dissolved in a solution of dioxane(150 mL), and ethanol(1 mL) and cooled to −5° C. To this is added HCl (5 equivalents; 4N indioxane) and the solution is stirred for one hour. The contents areconcentrated and the desired product is triturated from ether/hexane andfiltered to yield the desiredN-hydroxy-2(R)-[[(4-benzoylamino)benzenesulfonyl]-[(4-ethylmorpholino)-amino]-3-methylbutanamide,hydrochloride.

EXAMPLE 2N-Hydroxy-2(R)-[[(4-benzoylamino)benzenesulfonyl][(3-picolyl)amino]propanamide

Part A: To a solution of D-alanine methyl ester hydrochloride (6.0grams) in methanol (25 mL) is added 1.1 equivalents of3-Pyridinecarboxaldehyde. The solution is stirred at room temperaturefor several hours and then the solvent removed by rotary evaporation.The resulting imine is redissolved in acetic acid (10 mL) and methanol(2 mL), and sodium cyanoborohydride (1.5 equivalents) is added inseveral portions over 10 minutes. The mixture is then stirred for 16hours and then concentrated by rotary evaporation. The resulting residueis partitioned between ethyl acetate and aqueous sodium carbonate (10%).The organic layer is dried over magnesium sulfate, filtered andconcentrated to yield the desired N-3-picolyl-D-alanine methyl ester.

Part B: To a stirred solution of N-3-picolyl-D-alanine methyl ester (5.0g) in a 2:1 mixture of THF/water (200 mL) containing triethylamine (3equiv.) at 5° C. is added 4-(benzoylamino)benzenesulfonyl chloride andthe reaction is stirred to room temperature overnight. The resultingmixture is diluted with dichloromethane, and washed with 1 N HCl, andwater. The organic layer is dried over magnesium sulfate, filtered andconcentrated in vacuo to provide the desired methyl2(R)-[[(4-benzoylamino)benzenesulfonyl][(3-picolyl)amino]propionate as acrude product, which may be purified by silica gel chromatography usingethyl acetate/hexanes as eluant.

Part C: To a solution of methyl ester from Part B (2.0 grams) intetrahdrofuran (100 mL) is added a solution of aqueous 1N sodiumhydroxide (1.2 equiv.) and the reaction mixture is stirred for 20 hours.The solvents are removed by rotary evaporation and the remaining oil ispartitioned between ethyl acetate and 1N hydrochloric acid. The organiclayer is separated and dried over magnesium sulfate, filtered andconcentrated to yield2(R)-[[(4-benzoylamino)-benzenesulfonyl][(3-picolyl)amino]propionic-acid.

2(R)-[[(4-benzoylamino)benzenesulfonyl]-[(3-picolyl)amino]propionic acid(1.3 grams) and 1-hydroxybenzotriazole (1.5 equivalents) are dissolvedin anhydrous dimethylformamide (25 mL) and cooled to 10° C. To this isadded N-methylmorpholine (3 equivalents) followed by EDC (1.1equivalents) and this solution is stirred for two hours at 10° C. Tothis solution is added O-tetrahydropyranyl hydroxylamine (2 equivalents)and this solution is stirred overnight to room temperature. The solutionis diluted with water (100 mL) and extracted with ethyl acetate. Theorganic layer is washed with saturated sodium bicarbonate and brine,dried over magnesium sulfate, filtered and concentrated to yield thedesired O-THP protected hydroxamate which is further purified by silicagel chromatography to give a mixture of desired diastereomers which arecombined.

N-tetrahydropyranyloxy-2(R)-[[(4-benzoylamino)-benzenesulfonyl][(3-picolyl)amino]-propanamide(1.0 gram), is dissolved in a solution of dioxane (50 mL), and ethanol(1 mL) and cooled to −50° C. To this is added 5 equivalents of HCl (4Nin dioxane) and the solution is stirred for one hour. The contents areconcentrated and the desired product is triturated with ether/hexane andfiltered to yield the desiredN-hydroxy-2(R)-[[(4-benzoylamino)benzenesulfonyl]-[(3-picolyl)amino]propanamide,hydrochloride. This crude product may be purified by silica gelchromatography using methanol and methylene chloride as the eluant,after neutralization to the free base.

EXAMPLE 3N-Hydroxy-2(R)-[[(4-(benzenesulfonyl)amino)-benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanamide,Hydrochloride

Part A: To a stirred solution of D-valine (10.0 g) in a 2:1 mixture ofTHF/water (200 mL) containing triethylamine (3 equiv.) at 50° C. isadded 4-nitrobenzene-sulfonyl chloride (0.9 equiv.) and the reaction isstirred at room temperature overnight. The resulting mixture is dilutedwith dichloromethane, and washed with 1N HCl, and water. The organiclayer is dried over magnesium sulfate, filtered and concentrated invacuo to provide the desired N-(nitrobenzenesulfonyl)-(D)-valine as acrude amino acid product. A solution of the crude amino acid (10 grams)in dry toluene (80 mL) is charged with dimethylformamidedi-tertbutylacetal (45 mL) and heated to 100° C. for several hours. Theresulting cooled solution is concentrated by rotary evaporation andpurified by silica gel chromatography to provide the desiredN-(4-nitrobenzenesulfonyl)-(D)-valine, tert-butyl ester.

Part B: To a dimethylformamide solution (100 mL) of the tert-butyl esterfrom Part A (5.0 grams) is added 4-(2-chloroethyl)-morpholinehydrochloride (1.3 equivalents) and potassium carbonate (3 equivalents);and this suspension is heated to 70° C. for five hours. The resultingsuspension is cooled and diluted with water (500 mL) and extracted withethyl acetate. The organic layer is washed with water (2×200 mL),saturated sodium bicarbonate (2×200 mL), and brine, dried over magnesiumsulfate, filtered and concentrated to yield the desired product, t-butyl2(R)-[4-nitrobenzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoate,which can be purified by silica gel chromatography.

Part C: t-Butyl2(R)-[4-nitrobenzene-sulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoate(1.5 grams) is added to a Fisher® porter bottle containing ethanol/THF(50 mL each) and 200 mg of 10% palladium on carbon. The bottle isflushed with nitrogen while stirring and then charged with hydrogen at apressure of 50 psig. After one hour the bottle is flushed with nitrogenand the resulting suspension is filtered through Celite. The filtrate isconcentrated to yield t-butyl2(R)-[4-aminobenzenesulfonyl]-[(4-ethylmorpholino)amino]-3-methylbutanoate.

Part D: To a solution of t-butyl2(R)-[4-aminobenzenesulfonyl]-[(4-ethylmorpholino)amino]-3-methylbutanoatefrom Part C (1.30 grams) in tetrahydrofuran containingN-methylmorpholine (1.2 equivalents) is added benzenesulfonyl chloride(1.0 equivalents); this solution was stirred for 16 hours. The contentswere diluted with ethyl acetate and washed with 5% KHSO₄, saturatedsodium bicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated to yield the desiredt-butyl-2(R)-[[(4-(benzenesulfonyl)amino)-benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoate(1.5 grams).

Part E:t-Butyl-2(R)-[[(4-(benzenesulfonyl)amino)-benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoatefrom Part D (1.3 grams) in 50 mL of anhydrous dichloromethane is cooledto −5° C., and dry HCl gas is bubbled into the reaction flask for 20minutes. The flask is the sealed and allowed to warm to room temperatureover three to four hours. The solvent is removed by rotary evaporationand the desired acid, hydrochloride salt is triturated with ether hexaneand filtered. The dried precipitate is used without furtherpurification.

t-Butyl-2(R)-[[(4-(benzenesulfonyl)amino)-benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoate(1.0 grams) and 1-hydroxybenzotriazole (1.5 equivalents) are dissolvedin anhydrous dimethylformamide (25 mL) and cooled to 10° C. To this isadded N-methylmorpholine (3 equivalents) followed by EDC (1.1equivalents) and this solution is stirred for two hours at 10° C. Tothis solution is added O-tetrahydropyranyl (0-THP) hydroxylamine (2equivalents); this solution is stirred overnight at room temperature.The solution is diluted with water (100 mL) and extracted with ethylacetate. The organic layer is washed with saturated sodium bicarbonateand brine, dried over magnesium sulfate, filtered and concentrated toyield the desired O-THP-protected hydroxamate which is further purifiedby silica gel chromatography to give a mixture of desired diastereomerswhich are combined.

N-tetrahydropyranyloxy-2(R)-[[(4-(benzenesulfonyl)-amino)benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanoicacid (0.80 grams), is dissolved in a solution of dioxane (20 mL), andethanol (1 mL) and cooled to −5° C. To this is added HCl (5 equivalents;4N in dioxane) and the solution is stirred for one hour. The contentsare concentrated and the desired product is triturated from ether/hexaneand filtered to yield the desiredN-hydroxy-2(R)-[[(4-(benzenesulfonyl)amino)benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanamide,hydrochloride. This crude product may be purified by silica gelchromatography using methanol and methylene chloride as the eluant, onthe free base.

EXAMPLE 4(R)-N-[4-[[[2-(Hydroxyamino)-1-methyl-2-oxoethyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenyl]benzamide

Part A: To a solution of D-alanine, t-butyl ester hydrochloride (9.80 g,53.9 mmol) in H₂O (64 mL) and acetone (26 mL) was added triethylamine(17.3 mL, 124 mmol) and the solution was cooled to zero degrees Celsius.To this solution was added 4-nitrobenzenesulfonyl chloride (11.1 g, 50.2mmol) dropwise in acetone (25 mL). The solution was stirred for 72hours. The solution was concentrated in vacuo and the residue wasdissolved into ethyl acetate. The solution was washed with 5% KHSO₄,saturated NaHCO₃ and saturated NaCl and dried over Na₂SO₄.Recrystallization (ethyl acetate/hexane) provided the sulfonamide as asolid (10.87 g, 66%).

Part B: To a solution of the sulfonamide of part A (10.8 g, 32.7 mmol)in DMF (60 mL) was added 4-(2-chloroethyl)morpholine (12.2 g, 65.4 mmol)and K₂CO₃ (13.6 g, 98.0 mmol) and the solution was heated to seventydegrees Celsius for 7 hours. The solution was partitioned between ethylacetate and H₂O. The organic layer was washed with H₂O, saturated NaCland dried over Na₂SO₄. Concentration in vacuo followed by tritration(ethyl ether) provided the morpholine compound as a solid (8.48 g, 59%).MS(CI) MH⁺ calculated for C₁₉H₂₉N₃O₇S: 444, found: 444.

Part C: To a solution of the morpholine compound of part B (8.49 g, 19.1mmol) in THF (100 mL) under atmosphere of 50 psi of hydrogen was added4% Pd/C and the solution was stirred for 2 hours until uptake stopped.The solution was filtered through Celite and concentration in vacuo ofthe filtrate provided the aniline as a solid (8.5 g, quantitativeyield). MS(CI) MH⁺ calculated for C₁₉H₃₁N₃O₅S: 414, found: 414.

Part D: To a solution of the aniline of part C (2.0 g, 4.8 mmol) in THF(16 mL) was added triethylamine (3.0 mL, 21.3 mmol) and the solution wascooled to zero degrees Celsius. To this solution was added benzoylchloride (1.46 mL, 12.6 mmol) and the solution was stirred for 18 hoursat ambient temperature. The solution was concentrated in vacuo and theresidue was partitioned between ethyl acetate and saturated NaHCO₃. Theorganic layer was washed with saturated NaCl and dried over Na₂SO₄.Chromatography (on silica gel, ethyl acetate/methanol) provided thebenzamide as a solid (2.0 g, 80%). MS(CI) MH⁺ calculated forC₂₆H₃₅N₃O₆S: 518, found: 518.

Part E: To a solution of the benzamide of part D (2.0 g, 3.9 mmol) inanisole (9 mL) was added trifluoroacetic acid (26 mL) and the solutionwas stirred for 18 hours. The solution was concentrated in vacuo toremove the trifluoroacetic acid. The remaining solution was poured intoethyl ether and the resulting solid was collect by vacuum filtration toprovide the acid as a white solid (1.09 g, 50%) MS(CI) MH⁺ calculatedfor C₂₂H₂₇N₃O₆S: 462, found: 462.

Part F: To a solution of the acid of part E (1.09 g, 1.89 mmol) inmethanol (3 mL) cooled to zero degrees Celsius was added thionylchloride (0.18 mL, 2.4 mmol) and the solution was stirred at ambienttemperature for 18 hours. The solution was partitioned between ethylacetate and saturated NaHCO₃. The organic layer was washed withsaturated NaHCO₃ and saturated NaCl and dried over Na₂SO₄. Reverse phasechromatography (on silica; acetonitrile/H₂O) provided the methyl esteras a white solid (650 mg, 72%). MS(CI) MH⁺ calculated for C₂₃H₂₉N₃O₆S:476, found: 476.

Part G: To a solution of the methyl ester of part F (650 mg, 1.4 mmol)in methanol (1.6 mL) and THF (1.6 mL) was added 50% aqueoushydroxylamine (1.6 mL). The solution was stirred for 18 hours. Thesolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and H₂O. The organic layer was washed withsaturated NaCl and dried over Na₂SO₄. Concentration in vacuo provided(R)—N-[4-[[[2-(hydroxyamino)-1-methyl-2-oxoethyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenyl]benzamideas a white solid (380 mg, 58%). MS(CI) MH⁺ calculated for C₂₂H₂₈N₄O₆S:477, found: 477.

EXAMPLE 4a(R)-N-[4-[[[2-(Hydroxyamino)-1-methyl-2-oxoethyl][2-4-morpholinyl)ethyl]amino]sulfonyl]phenyl]benzamide,Monohydrochloride

To solution ofN-hydroxy-2(R)-[[(4-benzoylamino)benzenesulfonyl][(4-ethylmorpholino)amino]-3-methylbutanamide,hydrochloride of Example 1 (380 mg, 0.8 mmol) in acetonitrile (30 mL)was added (0.13 mL; 1.59 mmol) 12N HCl and the solution was stirred for10 minutes. The solution was concentrated in vacuo and the residue wastriturated with ethyl ether to provide the hydrochloride salt as a whitesolid (349 mg, 85%). MS(CI) MH⁺ calculated for C₂₂H₂₈N₄O₆S: 477, found:477.

EXAMPLE 5(R)-4-Bromo-N-[4-[[[2-(hydroxyamino)-1-methyl-2-oxoethyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenyl]benzamide,Mono(trifluoroacetate) (Salt)

Part A: To a solution of D-alanine, t-butyl ester hydrochloride (9.80 g,53.9 mmol) in H₂O (64 mL) and acetone (26 mL) was added triethylamine(17.3 mL, 124 mmol) and the solution was cooled to zero degrees Celsius.To this solution was added 4-nitrobenzenesulfonyl chloride (11.1 g, 50.2mmol) dropwise in acetone (25 mL). The solution was stirred for 72hours. The solution was concentrated in vacuo and the residue wasdissolved into ethyl acetate. The solution was washed with 5% KHSO₄,saturated NaHCO₃ and saturated NaCl and dried over Na₂SO₄.Recrystallization (ethyl acetate/hexane) provided the sulfonamide as asolid (10.87 g, 66%).

Part B: To a solution of the sulfonamide of part A (10.8 g, 32.7 mmol)in DMF (60 mL) was added 4-(2-chloroethyl)morpholine (12.2 g, 65.4 mmol)and K₂CO₃ (13.6 g, 98.0 mmol) and the solution was heated to seventydegrees Celsius for 7 hours. The solution was partitioned between ethylacetate and H₂O. The organic layer was washed with H₂O, saturated NaCland dried over Na₂SO₄. Concentration in vacuo followed by tritration(ethyl ether) provided the morpholine compound as a solid (8.48 g, 59%).MS(CI) MH⁺ calculated for C₁₉H₂₉N₃O₇S: 444, found: 444.

Part C: To a solution of the morpholine compound of part B (8.49 g, 19.1mmol) in THF (100 mL) under atmosphere of 50 psi of hydrogen was added4% Pd/C and the solution was stirred for 2 hours until uptake stopped.The solution was filtered through Celite and concentration in vacuo ofthe filtrate provided the aniline as a solid (8.5 g, quantitativeyield). MS(CI) MH⁺ calculated for C₁₉H₃₁N₃O₅S: 414, found: 414.

Part D: To a solution of the aniline of part C (2.84 g, 6.87 mmol) inTHF (40 mL) cooled to zero degrees Celsius was added triethylamine (2.1mL, 15.1 mmol) followed by 4-bromobenzoyl chloride (1.96 g, 9.93 mmol)in THF (5 mL). The solution was stirred at zero degrees Celsius for 1hour. The solution was concentrated in vacuo and the residue waspartitioned between ethyl acetate and saturated NaHCO₃ and the organicis washed with saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica gel, ethyl acetate/methanol) provided the benzamide as a solid(3.3 g, 81%). MS(CI) MH⁺ calculated for C₂₆H₃₄N₃O₆SBr: 596, found: 596.

Part E: To a solution of the benzamide of part D (2.84 g, 4.76 mmol) inanisole (11 mL) was added trifluoroacetic acid (32 mL) and the solutionwas stirred at ambient temperature for 18 hours. The solution wasconcentrated in vacuo to remove the trifluoroacetic acid and the residuewas poured into ethyl ether. Filtration provided the acid as anoff-white solid (2.8 g, quantitative yield). MS(CI) MH⁺ calculated forC₂₂H₂₆N₃O₆SBr: 541, found 541.

Part F: To a solution of the acid of part E (2.71 g, 4.14 mmol) inmethanol (10 mL) cooled to zero degrees Celsius was added thionylchloride (0.38 mL, 5.25 mmol). The solution was stirred for 18 hours atambient temperature. The solution was partitioned between ethyl acetateand saturated NaHCO₃ and the organic layer was washed with saturatedNaCl and dried over Na₂SO₄. Chromatography (on silica, ethylacetate/methanol) provided the methyl ester as a solid (1.96 g, 85%).

Part G: To a solution of the methyl ester of part F (1.96 g, 3.53 mmol)in THF (2 mL) and methanol (2 mL) was added 50% aqueous hydroxylamine(4.2 mL, 70.7 mmol) was added and the solution was stirred for 18 hoursat ambient temperature. The solution was concentrated in vacuo andreverse phase chromatography (on silica, acetonitrile/H₂O (0.05% TFA))provided(R)-4-bromo-N-[4-[[[2-(hydroxyamino)-1-methyl-2-oxoethyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenyl]benzamide,mono(trifluoroacetate) salt as a white solid (350 mg, 18%). MS(EI) M⁺calculated for C₂₂H₂₇N₄O₆SBr: 555, found: 555.

EXAMPLE 6(R)-N-[4-[[[2-(Hydroxyamino)-1-methyl-2-oxoethyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenyl]cyclohexanecarboxamide,Mono(trifluoroacetate) (Salt)

Part A: To a solution of D-alanine, t-butyl ester hydrochloride (9.80 g,53.9 mmol) in H₂O (64 mL) and acetone (26 mL) was added triethylamine(17.3 mL, 124 mmol) and the solution was cooled to zero degrees Celsius.To this solution was added 4-nitrobenzene-sulfonyl chloride (11.1 g,50.2 mmol) dropwise in acetone (25 mL). The solution was stirred for 72hours. The solution was concentrated in vacuo and the residue wasdissolved into ethyl acetate. The solution was washed with 5% KHSO₄,saturated NaHCO₃ and saturated NaCl and dried over Na₂SO₄.Recrystallization (ethyl acetate/hexane) provided the sulfonamide as asolid (10.87 g, 66%).

Part B: To a solution of the sulfonamide of part A (10.8 g, 32.7 mmol)in DMF (60 mL) was added 4-(2-chloroethyl)morpholine (12.2 g, 65.4 mmol)and K₂CO₃ (13.6 g, 98.0 mmol) and the solution was heated to seventydegrees Celsius for 7 hours. The solution was partitioned between ethylacetate and H₂O. The organic layer was washed with H₂O, saturated NaCl,and dried over Na₂SO₄. Concentration in vacuo followed by tritration(ethyl ether) provided the morpholine compound as a solid (8.48 g, 59%).MS(CI) MH⁺ calculated for C₁₉H₂₉N₃O₇S: 444, found: 444.

Part C: To a solution of the morpholine compound of part B (8.49 g, 19.1mmol) in THF (100 mL) under atmosphere of 50 psi of hydrogen was added4% Pd/C and the solution was stirred for 2 hours until uptake stopped.The solution was filtered through Celite and concentration in vacuo ofthe filtrate provided the aniline as a solid (8.5 g, quantitativeyield). MS(CI) MH⁺ calculated for C₁₉H₃₁N₃O₅S: 414, found: 414.

Part D: To a solution of the aniline of part C (2.70 g, 6.53 mmol) inTHF (40 mL) was added triethylamine (3.6 mL, 26.1 mmol) and the solutionwas cooled to zero degrees Celsius. To this solution was addedcyclohexane carbonyl chloride (2.3 mL, 17.0 mmoL) and the solution wasstirred for 30 minutes. The solution was concentrated in vacuo and theresidue was partitioned between ethyl acetate and saturated NaHCO₃. Theorganic layer was washed with saturated NaHCO₃ and saturated NaCl, anddried over Na₂SO₄. Chromatography (on silica, ethyl acetate/methanol)provided the benzamide as a solid (2.09 g, 61%). MS(CI) MH⁺ calculatedfor C₂₆H₄₁N₃O₆S: 524, found: 524.

Part E: To a solution of the benzamide of part D (2.0 g, 3.82 mmol) inanisole (10 mL) was added trifluoroacetic acid (18 mL). The solution wasstirred for 18 hours at ambient temperature. The solution wasconcentrated in vacuo to remover the trifluoroacetic acid. The remainingsolution was diluted with ethyl ester and the resulting white solid wascollected by vacuum filtration to provide the acid (2.48 g, quantitativeyield). MS(CI) MH⁺ calculated for C₂₂H₃₃N₃O₆S: 468, found: 468.

Part F: To a solution of the acid of part E (1.27 g, 2.18 mmol) in DMF(10 mL) was added N-hydroxybenzotriazole (353 mg, 2.62 mmol) followed by4-methylmorpholine (1.4 mL, 13.1 mmol), tetrahydropyranyl hydroxylamine(791 mg, 6.76 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (590 mg, 3.05 mmol). The solution was stirred for 72hours. The solution was partitioned between ethyl acetate and saturatedNaHCO₃ and the organic was washed with H₂O and saturated NaCl and driedover Na₂SO₄. Chromatography (on silica, ethyl acetate/methanol) providedthe ester as a white solid (1.2 g, quantitative yield). MS(CI) MH⁺calculated for C₂₇H₄₂N₄O₇S: 567, found 567.

Part G: A solution of the ester of part F (1.2 g, 2.12 mmol) in 4N HClin dioxane (25 mL) was stirred for 1 hour. The solution was diluted withethyl ether and resulting white solid was collected by vacuumfiltration. The solid was suspended into ethyl acetate and was washedwith saturated NaHCO₃ and saturated NaCl and dried over Na₂SO₄. Reversephase chromatography (on silica, acetonitrile/H₂O (0.05% TFA)) provided(R)-N-[4-[[[2-(hydroxyamino)-1-methyl-2-oxoethyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]-phenyl]cyclohexane-carboxamide,mono(trifluoroacetate) salt as a white solid (312 mg, 25%). MS(CI) MH⁺calculated for C₂₂H₃₄N₄O₆S: 483, found 483.

EXAMPLE 7(R)-N-4-[[[1-[(Hydroxyamino)carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]-phenyl]-4-propylbenzamide,Monohydrochloride

Part A: To a solution to D-valine (25.0 g, 213 mmol) in H₂O (180 mL) andacetone (96 mL) was added triethylamine (62 mL, 448 mmol) and was cooledto zero degrees Celsius. To this solution was added4-nitrobenzenesulfonyl chloride (45.3 g, 204 mmol) in acetone (100 mL)dropwise. The solution was stirred for 72 hours. The solution wasconcentrated in vacuo and the resulting aqueous layer was extracted withtoluene and acidified to pH=2 with 2N HCl. The aqueous layer wasextracted with ethyl acetate three times and the combined organic layerswere washed with saturated NaCl and dried over MgSO₄. Concentration invacuo provided the sulfonamide as a light brown solid (37.15 g, 61%).

Part B: A solution of the sulfonamide of part A (37.15 g, 123 mmol) anda catalytic amount of H₂SO₄ in dichloromethane/dioxane (1 L) wassubjected to isobutylene for 18 hours. The solution was cooled to zerodegrees Celsius and quenched with saturated NaHCO₃. The aqueous layerwas extracted with ethyl acetate and the organic layer was washed withsaturated NaCl and dried over MgSO₄. Chromatography (on silica, ethylacetate/hexane) provided the t-butyl ester as a solid (16.7 g, 38%).

Part C: To a solution of the t-butyl ester of part B (16.5 g, 46 mmol)in DMF (60 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (17.2g, 92 mmol) and K₂CO₃ (25.5 g, 184 mmol) and the solution was heated tosixty degrees Celsius for 7 hours. The solution was partitioned betweenethyl acetate and H₂O and the organic layer was washed with saturatedNaCl and dried over Na₂SO₄. Chromagraphy (on silica, ethylacetate/hexane) provided the morpholine compound as a solid (21.5 g,99%).

Part D: To a solution of the morpholine compound of part C (21.5 g, 45.6mmol) in THF (200 mL) in a flask purged with H₂ was added 4% Pd/C (3.04g) and the solution was hydrogenated until uptake ceased. The solutionwas filtered through Celite® to remove the excess catalyst and thefiltrate was concentrated in vacuo to provide the aniline as an oil(19.2 g, 95%).

Part E: To a solution of the aniline of part D (2.9 g, 6.6 mmol) in THF(20 mL) was added triethylamine (3.66 mL, 26.3 mmol) and cooled to fourdegrees Celsius. To this solution was added 4-propylbenzoyl chloride(2.0 g, 11.0 mmol) and the solution was stirred for 1 hour at ambienttemperature. The solution was concentrated in vacuo and the residue waspartitioned between ethyl acetate and saturated NaHCO₃. The organiclayer was washed with saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the benzamideas a solid (3.3 g, 85%).

Part F: To a solution of the benzamide of part E (3.2 g, 5.4 mmol) indichloromethane (20 mL) was added trifluoroacetic acid (80 mL) and thesolution was stirred for 30 minutes. The solution was concentrated invacuo and the residue was dissolved into warm toluene/ethyl acetate andwas added dropwise to ethyl ether to produce a yellow precipitate.Vacuum filtration provided the acid as a yellow solid (2.58 g, 84%).

Part G: To a solution of the acid of part F (2.04 g, 3.6 mmol) in DMF (5mL) was added N-hydroxybenzotriazole (583 mg, 4.32 mmol),4-methylmorpholine (2.37 mL, 21.6 mmol), tetrahydropyranyl hydroxylamine(1.31 g, 11.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (966 mg, 5.04 mmol). The solution was stirred for 18 hoursat ambient temperature. The solution was partitioned between ethylacetate and saturated NaHCO₃. The organic layer was washed withsaturated NaHCO₃, H₂O and saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/methanol) provided the ester asa solid (2.15 g, 95%).

Part H: Into a solution of the ester of part G (2.15 g, 3.4 mmol) inmethanol (30 mL) was bubbled HCl gas. After 1 hour the solution wasconcentrated in vacuo to a reduced volume (5 mL) and this solution wasdropped into cooled ethyl ether to produce a precipitate. Vacuumfiltration provided(R)-N-4-[[[1-[(hydroxyamino)carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]-phenyl]-4-propylbenzamide,monohydrochloride as a white solid (1.64 g, 83%). MS(CI) MH⁺ calculatedfor C₂₇H₃₈N₄O₆S: 547, found 547.

EXAMPLE 8(R)-4-Butyl-N-[4-[[[1-[(hydroxyamino)-carbonyl]-2-methylpropyl][2-(4-morpholinyl)-ethyl]amino]sulfonyl]phenyl]benzamide,Monohydrochloride

Part A: To a solution of the aniline of Example 7, part D (2.53 g, 5.73mmol) in THF (20 mL) was added triethylamine (3.2 mL, 22.9 mmol) and thesolution was cooled to four degrees Celsius. To this solution was added4-butylbenzoyl chloride (1.9 g, 9.7 mmol) and the solution was stirredat ambient temperature for 18 hours. The solution was concentrated invacuo and the residue was partitioned between ethyl acetate andsaturated NaHCO₃. The organic layer was washed with saturated NaHCO₃ andsaturated NaCl and dried over Na₃SO₄. Chromatography (on silica, ethylacetate/hexane) provided the benzamide as a solid (2.8 g, 82%)

Part B: A solution of the benzamide of part A (2.8 g, 4.6 mmol) in 4NHCl in dioxane (20 mL) was stirred for 72 hours at ambient temperature.The solution was concentrated in vacuo and the residue was dissolved indioxane (3 mL) and dropped into stirring ethyl ether. The resultingprecipitate was collected by vacuum filtration to provide the acid as awhite solid (2.7 g, quantitative yield).

Part C: To a solution of the acid of part B (2.0 g, 3.4 mmol) in DMF (5mL) was added N-hydroxybenzotriazole (557 mg, 4.13 mmol) and thesolution was cooled to four degrees Celsius. To this solution was added4-methylmorpholine (2.27 mL, 20.6 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (923 mg,4.81 mmol) and tetrahydropyranyl hydroxylamine (604 mg, 5.16 mmol) andthe solution was stirred for 1 hour. The solution was partitionedbetween ethyl acetate and saturated NaHCO₃. The organic layer was washedwith saturated NaHCO₃, H₂O and saturated NaCl, and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/methanol) provided the ester asa solid (2.0 g, 91%).

Part D: To a solution of the ester of part C (2.0 g, 3.1 mmol) inmethanol (1.5 mL) was added 4N HCl in dioxane (10 mL) and the solutionwas stirred for 18 hours. The solution was concentrated in vacuo to asmaller volume and dropped into ethyl ether. The resulting precipitatewas collected by vacuum filtration to provide(R)-4-butyl—N-[4-[[[1-[(hydroxyamino)-carbonyl]-2-methylpropyl][2-(4-morpholinyl)-ethyl]amino]sulfonyl]phenyl]benzamide,monohydrochloride as a white solid (1.8 g, 96%). MS(CI) MH⁺ calculatedfor C₂₈H₄₀N₄O₆S: 561, found: 561.

EXAMPLE 9R-N-[4-[[[1-(Hydroxyamino)carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]amino]-sulfonyl]phenyl]-4-pentylbenzamide,Monohydrochloride

Part A: To a solution of the aniline of Example 7, part D (2.60 g, 5.88mmol) in THF (20 mL) was added triethylamine (3.2 mL, 22.8 mmol) and thesolution was cooled to four degrees Celsius. To this solution was added4-pentylbenzoyl chloride (2.1 g, 10.0 mmol) and the solution was stirredfor 18 hours at ambient temperature. The solution was concentrated invacuo and the residue was partitioned between ethyl acetate andsaturated NaHCO₃. The organic layer was washed with saturated NaHCO₃ andsaturated NaCl and dried over Na₂SO₄. Chromatography (ethylacetate/hexane) provided the benzamide as a solid (2.09 g, 58%).

Part B: A solution of the benzamide of part A (2.09 g, 3.4 mmol) in 4NHCl (20 mL) was stirred for 72 hours. The solution was concentrated invacuo and the residue was dissolved into ethyl acetate (5 mL) anddropped into ethyl ether. The resulting precipitate was collected byvacuum filtration to provide the acid as a solid (1.9 g, 94%).

Part C: To a solution of the acid of part B (1.52 g, 2.56 mmol) in DMF(5 mL) was added N-hydroxybenzotriazole (414 mg, 3.07 mmol) and thesolution was cooled to four degrees Celsius. To this solution was added4-methylmorpholine (1.69 mL, 15.6 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (687 mg,3.58 mmol) and tetrahydropyranyl hydroxylamine (449 mg, 3.84 mmol) andwas stirred for 1 hour at ambient temperature. The solution waspartitioned between ethyl acetate and saturated NaHCO₃ and the organiclayer was washed with saturated NaHCO₃, saturated NaCl and H₂O and driedover Na₂SO₄. Chromatography (ethyl acetate/methanol) provided the esteras a solid (1.54 g, 91%).

Part D: To a solution of the ester of part C (1.54 g, 2.34 mmol) inmethanol (1 mL) was added 4N HCl (10 mL) and the solution was stirredfor 18 hours at ambient temperature. The solution was concentrated invacuo. Reverse phase chromatography (on silica, acetonitrile/H₂O (HCl)provided the title compound,R-N-[4-[[[1-(hydroxyamino)carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenyl]-4-pentylbenzamide,monohydrochloride, as a white solid (745 mg, 52%). MS(CI) MH⁺ calculatedfor C₂₉H₄₂N₄O₆S: 575, found: 575.

EXAMPLE 10(R)-4-Hexyl-N-[4-[[[1-(hydroxyamino)-carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenylbenzamide,Monohydrochloride

Part A: To a solution of the aniline of Example 7, part D (2.5 g, 5.7mmol) was added triethylamine (3.2 mL, 22.8 mmol) and the solution wascooled to four degrees Celsius. To this solution was added4-hexylbenzoyl chloride (2.18 g, 9.69 mmol) and the solution was stirredovernight at ambient temperature. The solution was concentrated in vacuoand the residue was partitioned between ethyl acetate .and saturatedNaHCO₃. The organic layer was washed with saturated NaHCO₃ and saturatedNaCl and dried over Na₂SO₄. Chromatography (on silica, ethylacetate/hexane) provided the benzamide as a solid (2.76 g, 77%).

Part B: A solution of the benzamide of part A (2.7 g, 4.3 mmol) in 4NHCl in dioxane (20 mL) was stirred for 72 hours. The solution wasconcentrated in vacuo and the residue was dissolved into ethyl acetate(5 mL). This solution was dropped into ethyl ether. The resultingprecipitate was collected by vacuum filtration to provide the acid as asolid (2.5 g, 95%).

Part C: To a solution of the acid of part B (2.03 g, 3.33 mmol) in DMF(5 mL) was added N-hydroxybenzotriazole (540 mg, 4.00 mmol) and thesolution was cooled to four degrees Celsius. To this solution was added4-methylmorpholine (2.19 mL, 20.0 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (894 mg,4.66 mmol) and tetrahydropyranyl hydroxylamine (615 mg, 5.00 mmol) andthe solution was stirred for 1 hour at ambient temperature. The solutionwas partitioned between ethyl acetate and saturated NaHCO₃ and theorganic layer was washed with saturated NaHCO₃, saturated NaCl and H₂Oand dried over Na2SO₄. Chromatography (on silica, ethylacetate/methanol) provided the ester as a solid (2.01 g, 90%).

Part D: To a solution of the ester of part C (2.01 g, 3.24 mmol) inmethanol (1 mL) was added 4N HCl (10 mL) and the solution was stirredfor 18 hours at ambient temperature. Reverse phase chromatography (onsilica, acetonitrile/H₂O (0.05% HCl)) provided the title compound,(R)-4-hexyl-N-[4-[[[1-(hydroxyamino)carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]-phenylbenzamide,monohydrochloride, as a white solid (1.23 g, 61%). MS(CI) MH⁺ calculatedfor C₃₀H₄₄N₄O₆S: 589, found: 589.

EXAMPLE 10a(R)-4-Hexyl-N-[4-[[[1-(hydroxyamino)-carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenylbenzamide

To a solution of the methyl ester of Example 10, part C (1.4 mmol) inmethanol (1.6 mL) and THF (1.6 mL) is added 50% aqueous hydroxylamine(1.6 mL). The solution is stirred for 18 hours. The solution isconcentrated in vacuo and the residue was partitioned between ethylacetate and H₂O. The organic layer is washed with saturated NaCl anddried over Na₂SO₄. Concentrationof the dried organic layer in vacuoprovides “10-Hydrochloride. MS(CI) MH⁺ calculated for C₃₀H₄₄N₄O₆S: 589.

EXAMPLE 11(R)-N-[4-[[[1-[(Hydroxyamino)carbonyl]-2-methylpropyl](3-pyridinylmethyl)amino]sulfonyl]phenyl]-4-propylbenzamide

Part A: To a solution of aniline (3.3 g, 35.7 mmol) and triethylamine(8.0 g, 79 mmol) in THF, cooled to zero degrees Celsius, was addedbenzoyl chloride (5.0 g, 27 mmol) and the solution was stirred for 18hours at ambient temperature. The solution was diluted with H₂O andextracted with ethyl acetate. The organic layer was washed with 1N HCland saturated NaHCO₃ and dried over MgSO₄. Recrystallization (ethylacetate/hexane) provided the benzamide as an off-white solid (4.91 g,64%).

Part B: To chlorosulfonic acid (2.0 g, 17.3 mmol) cooled to five degreesCelsius was added the benzamide of part A (4.91 mg, 17.3 mmol). Thesolution was heated to sixty-five degrees Celsius for 1 hour. Thesolution was cooled to ambient temperature and diluted withdichloromethane. The solution was poured into cold H₂O and extractedwith ethyl acetate. The organic layer was washed with saturated NaHCO₃and dried over MgSO₄. Concentration in vacuo provided the sulfonylchloride as a yellow solid (4.89 g, 74%).

Part C: To a solution of D-valine, t-butyl ester (2.6 g, 15.1 mmol) inTHF (25 mL) was added the sulfonyl chloride of part B (4.8 g, 12.5 mmol)followed by triethylamine (6.3 mL, 44.5 mmol) and the solution wasstirred for 18 hours at ambient temperature. The solution was dilutedwith H₂O and the resulting precipitate was collected by vacuumfiltration. The solid was dissolved into ethyl acetate anddichloromethane and dried over Na₂SO₄. Concentration in vacuo providedthe sulfonamide (4.0 g, 67%).

Part D: To a solution the sulfonamide of part C (2.0 g, 4.1 mmol) in DMF(10 mL) was added K₂CO₃ (2.2 g, 16 mmol) followed by picolyl chloridehydrochloride (860 mg, 5.0 mmol) and the solution was stirred for 40hours at ambient temperature. The solution was partitioned between ethylacetate and H₂O. The organic layer was chromatographed (on silica, ethylacetate/hexane) to provide the picolyl compound (1.3 g, 57%).

Part E: To a solution of the picolyl compound of part D (1.1 g, 2 mmol)in dichloromethane (15 mL) was added trifluoroacetic acid (20 mL) andthe solution was stirred for 20 minutes. Concentration in vacuo providedthe acid as a solid (1.24 mg, quantitative yield).

Part F: To a solution of the acid of part E (1.2 g, 2.0 mmol) in DMF (20mL) was added 4-methylmorpholine (1.2 g, 12 mmol),N-hydroxybenzotriazole (800 mg, 3 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (780 mg, 4mmol). After 10 minutes of stirring, tetrahydropyranyl hydroxylamine(720 mg, 6 mmol) was added and the solution was stirred for 18 hours.The solution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and ₂O. The organic layer was dried over MgSO₄.Chromatography (on silica, ethyl acetate/hexane/methanol) provided theester as an oil (1.4 g, quantitative yield).

Part G: A solution of the ester of part F (1.4 g, 2 mmol) in dioxane (5mL) and 4M HCl in dioxane (10 mL) was stirred for 30 minutes. Dilutionwith ethyl ether which precipitated a white solid followed by collectionby vacuum filtration provided the title compound,(R)-N-[4-[[[1-[(hydroxyamino)carbonyl]-2-methylpropyl](3-pyridinylmethyl)amino]sulfonyl]phenyl]-4-propylbenzamide(1.28 g, 2.3 mmol). MS(CI) MH⁺ calculated for C₂₇H₃₂N₄O₅S: 525, found:525.

EXAMPLE 12(R)-N-[4-[[[1-(Hydroxyamino)carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]-amino]sulfonyl]phenyl]benzamide,Monohydrochloride

Part A: To a solution of the aniline of Example 7, part D (2.2 g, 5.0mmol) in dichloromethane (5 mL) was added triethylamine (1.0 g, 10 mmol)and the solution was cooled to zero degrees Celsius. To this solutionwas added benzoyl chloride (717 mg, 5.1 mmol) in dichloromethane (5 mL).The solution was stirred for 16 hours at ambient temperature. Thesolution was diluted with dichloromethane and washed with saturatedNaHCO₃ and saturated NaCl and dried over Na₂SO₄. Chromatography (onsilica, ethyl acetate/hexane) provided the benzamide as a solid (2.7 g,99%).

Part B: To a solution of the benzamide of part A (2.56 g, 4.69 mmol) indichloromethane (50 mL) was added trifluoroacetic acid (12 mL) and thesolution was stirred for 18 hours at ambient temperature. The solutionwas concentrated in vacuo. Chromatography (on silica, ethylacetate/methanol) provided the acid as a solid (1.64 g, 71%).

Part C: To a solution of the acid of part C (1.24 g, 2.53 mmol) in DMF(15 mL) was added N-hydroxybenzotriazole (513 mg, 3.8 mmol) and4-methylmorpholine (1.5 g, 15.2 mmol) and the solution was cooled tozero degrees Celsius. To this solution was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (534 mg,2.78 mmol) and tetrahydropyranyl hydroxylamine (444 mg, 3.8 mmol) andthe solution was stirred for 18 hours at ambient temperature. Thesolution was diluted with H₂O and the solution was extracted with ethylacetate. The organic layer was washed with saturated NaHCO₃ andsaturated NaCl and dried over Na₂SO₄. Chromatography (on silica, ethylacetate/hexane/methanol) provided the ester as a solid (815 mg, 55%).

Part D: To a solution of the ester of part C (750 mg, 1.27 mmol) indioxane (5 mL) was added 4N HC1 in dioxane (10 mL) and the solution wasstirred for 20 minutes at ambient temperature. Trituration (hexane)provided the title compound,(R)-N-[4-[[[1-(hydroxyamino)carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]-amino]sulfonyl]phenyl]benzamide,monohydrochloride, as a white solid (590 mg, 86%). MS(CI) MH⁺ calculatedfor C₂₄H₃₂N₄O₆S: 505, found: 505.

EXAMPLE 13(R)-4-Bromo-N-[4-[[[1-(hydroxyamino)carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenylbenzamide,Monohydrochloride

Part A: To a solution of the aniline of Example 7, part D (2.2 g, 5mmol) in dichloromethane (50 mL) was added triethylamine (1.5 g, 15mmol) and 4-bromobenzoyl chloride (1.65 g, 7.5 mmol) and the solutionwas stirred for 12 hours at ambient temperature. The solution wasdiluted with dichloromethane and washed with saturated NaHCO₃ andsaturated NaCl and dried over Na₂SO₄. Chromatography (on silica, ethylacetate/hexane) provided the benzamide as a solid (2.8 g, 90%).

Part B: To a solution of the benzamide of part A (2.5 g, 4.0 mmol) indichloromethane (4 mL) was added trifluoroacetic acid (16 mL) and thesolution was stirred for 16 hours at ambient temperature. The solutionwas concentrated in vacuo and chromatography (on silica, ethylacetate/methanol) provided the acid as a solid (1.68 g, 74%).

Part C: To a solution of the acid of part B (1.2 g, 2.11 mmol) in DMF(20 mL) was added N-hydroxybenzotriazole (428 mg, 3.16 mmol) and4-methylmorpholine (1.3 g, 12.7 mmol) and the solution was cooled tozero degrees Celsius. To this solution was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (445 mg,2.32 mmol) and tetrahydropyranyl hydroxylamine (371 mg, 3.16 mmol) andthe solution was stirred for 18 hours at ambient temperature. Thesolution was diluted with H₂O and the solution was extracted with ethylacetate. The organic layer was washed with saturated NaHCO₃ andsaturated NaCl and dried over Na₂SO₄. Chromatography (on silica, ethylacetate/hexane/methanol) provided the ester as a solid (940 mg, 67%).

Part D: To a solution of the ester of part C (800 mg, 1.2 mmol) indioxane (5 mL) was added 4N HCl in dioxane (10 mL) and the solution wasstirred for 20 minutes at ambient temperature. Trituration (hexane)provided the title compound,(R)-4-bromo—N-[4-[[[1-(hydroxyamino)carbonyl]-2-methylpropyl][2-(4-morpholinyl)ethyl]amino]sulfonyl]phenylbenzamide,monohydrochloride, as a white solid (668 mg, 90%). MS(CI) MH⁺ calculatedfor C₂₄H₃₁N₄O₆SBr: 584, found: 584.

EXAMPLE 14(R)-N-Hydroxy-α-[[[4-(4-pentylbenzoyl)amino]phenyl]sulfonyl]aminoBenzenepropanamide

Part A: To a solution of aniline (3.3 9, 35.7 mmol) and triethylamine(8.0 g, 79 mmol) in THF, cooled to zero degrees Celsius, was added4-pentylbenzoyl chloride (5.7 g, 27 mmol) and the solution was stirredfor 18 hours at ambient temperature. The solution was diluted with H₂Oand extracted with ethyl acetate. The organic layer was washed with 1NHCl and saturated NaHCO₃ and dried over MgSO₄. Recrystallization (ethylacetate/hexane) provided the benzamide as an off-white solid.

Part B: To chlorosulfonic acid (2.3 g, 20 mmol) cooled to five degreesCelsius was added the benzamide of part A. The solution was heated tosixty-five degrees Celsius for 1 hour. The solution was cooled toambient temperature and diluted with dichloromethane. The solution waspoured into cold H₂O and extracted with ethyl acetate. The organic layerwas washed with saturated NaHCO₃ and dried over MgSO₄. Concentration invacuo provided the sulfonyl chloride as a yellow solid (5.5 g, 55%, twosteps).

Part C: To a solution of R-phenylalanine (2.47 g, 15 mmol) in THF (100mL) and H₂O (30 mL) cooled to zero degrees Celsius was addedtriethylamine (4.54 g, 45 mmol) and the sulfonyl chloride of part B (5.5g, 15 mmol) and the solution was stirred for 16 hours at ambienttemperature. The solution was concentrated in vacuo and extracted withethyl acetate. The organic layer was washed with saturated NaCl.Chromatography (on silica, ethyl acetate/hexane) provided thesulfonamide as a solid (4.5 g, 61%).

Part D: To a solution of the sulfonamide of part C (494 mg, 1.0 mmol) inDMF (20 mL) was added N-hydroxybenzotriazole (203 mg, 1.5 mmol) and thesolution was cooled to ten degrees Celsius. To this solution was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (211 mg, 1.1mmol) and tetrahydropyranyl hydroxylamine (351 mg, 3.0 mmol) and thesolution was stirred for 12 hours at ambient temperature. The solutionwas diluted with H₂O and the resulting precipitate was extracted withethyl acetate and washed with saturated NaCl and dried over Na₂SO₄.Chromatography (ethyl acetate/hexane) provided the ester as a solid (327mg, 57%).

Part E: To a solution of the ester of part D (200 mg, 0.34 mmol) indioxane (3 mL) was added 4N HCl in dioxane (5 mL) and the solution wasstirred for 1 hour at ambient temperature. The solution was concentratedin vacuo and reverse phase chromatography (acetonitrile/H₂O) providedthe title compound,(R)-N-hydroxy-α-[[[4-(4-pentylbenzoyl)amino]phenyl]sulfonyl]aminobenzenepropanamide, as a white solid (80 mg, 26%). MS(CI) MH⁺ calculatedfor C₂₇H₃₁N₃O₅S: 510, found: 510.

EXAMPLE 15(R)-N-Hydroxy-α-[[2-(4-morpholinyl)ethyl]-[[4-[(4-pentylbenzoyl)amino]phenyl]sulfonyl]amino]benzenepropanamide,Monohydrochloride

Part A: To a solution of the sulfonamide of Example 14, part C (7.0 g,15 mmol) in toluene (120 mL) was added DMF di-tert-butylacetal (6.1 g,30 mmol) and the solution was heated at one hundred degrees Celsius for1 hour. Concentration in vacuo followed by recrystallization (coldmethanol) provided the ester as a solid (3.7 g, 45%).

Part B: To a solution of the ester of part A (3.5 g, 6.35 mmol) andK₂CO₃ (5.53 g, 40 mmol) in DMF (100 mL) was added4-(2-chloroethyl)morpholine hydrochloride (1.77 g, 9.52 mmol) and thesolution was stirred for 16 hours at sixty degrees Celsius. The solutionwas partitioned between ethyl acetate and H₂O and the organic layer waswashed with saturated NaCl and dried over Na₂SO₄. Chromatography (ethylacetate/hexane) provided the morpholine compound as a solid (1.8 g,43%).

Part C: To a solution of the morpholine compound of part B (1.4 g, 2.1mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (12 mL)and the solution was stirred for 16 hours at ambient temperature.Concentration in vacuo followed by reverse phase chromatography(acetonitrile/H₂O) provided the acid as a solid (1.12 g, 87%).

Part D: To a solution of the acid of part C (607 mg, 1.0 mmol) in DMF(40 mL) was added N-hydroxybenzotriazole (207 mg, 1.5 mmol) and thesolution was cooled to two degrees Celsius. To this solution was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (211 mg, 1.1mmol) and tetrahydropyranyl hydroxylamine (585 mg, 5.0 mmol) and thesolution was stirred for 6 hours at ambient temperature. The solutionwas diluted with H₂O and the resulting precipitate was extracted withethyl acetate and washed with saturated NaCl and dried over Na₂SO₄.Chromatography (on silica, ethyl acetate/hexane) provided the ester as asolid.

Part E: To a solution of the ester of part D in dioxane (3 mL) was added4N HCl in dioxane (5 mL) and the solution was stirred for 1 hour atambient temperature. The solution was concentrated in vacuo and reversephase chromatography (acetonitrile/H₂O) provided the title compound,(R)—N-hydroxy-α-[[2-(4-morpholinyl)ethyl]-[[4-[(4-pentylbenzoyl)amino]phenyl]-sulfonyl]amino]benzenepropanamide,monohydrochloride, as a white solid (80 mg, 12%, two steps). MS(CI) MH⁺calculated for C₃₃H₄₂N₄O₆S: 660, found: 660.

EXAMPLE 16 In Vitro Metalloprotease Inhibition

The compounds prepared in the manner described in Examples 1 to 15 wereassayed for activity by an in vitro assay. Following the procedures ofKnight et al., FEBS Lett. 296(3):263 (1992). Briefly,4-aminophenylmercuric acetate (APMA) or trypsin activated MMPs wereincubated with various concentrations of the inhibitor compound at roomtemperature for 5 minutes.

More specifically, recombinant human MMP-13 and MMP-1 enzymes wereprepared in laboratories of the assignee. MMP-13 was expressed inbaculovirus as a proenzyme, and purified first over a heparin agarosecolumn and then over a chelating zinc chloride column. The proenzyme wasactivated by APMA for use in the assay. MMP-1 expressed in transfectedHT-1080 cells was provided by Dr. Howard Welgus of WashingtonUniversity, St. Louis, Mo. The enzyme was also activated using APMA andwas then purified over a hydroxamic acid column.

The enzyme substrate is a methoxycoumarin-containing polypeptide havingthe following sequence:

MCA-ProLeuGlyLeuDpaAlaArgNH², wherein MCA is methoxycoumarin and Dpa is3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl alanine. This substrate iscommercially available from Baychem as product M-1895.

The buffer used for assays contained 100 mM Tris-HCl, 100 mM NaCl, 10 mMCaCl₂ and 0.05 percent polyethyleneglycol (23) lauryl ether at a pHvalue of 7.5. Assays were carried out at room temperature, and dimethylsulfoxide (DMSO) at a final concentration of 1 percent was used todissolve inhibitor compound.

The assayed inhibitor compound in DMSO/buffer solution was compared toan equal amount of DMSO/buffer with no inhibitor as control usingMicrofluor™ White Plates (Dynatech). The inhibitor or control solutionwas maintained in the plate for 10 minutes and the substrate was addedto provide a final concentration of 4 μM.

In the absence of inhibitor activity, a fluorogenic peptide was cleavedat the gly-leu peptide bond, separating the highly fluorogenic peptidefrom a 2,4-dinitrophenyl quencher, resulting in an increase offluorescence intensity (excitation at 328 nm/emission at 415 nm).Inhibition was measured as a reduction in fluorescent intensity as afunction of inhibitor concentration, using a Perkin Elmer L550 platereader. The IC₅₀ values were calculated from those values. The resultsare set forth in the Inhibition Table below as Table 9, reported interms of IC₅₀.

TABLE 9 INHIBITION TABLE hMMP-1 hMMP-2 hMMP-3 hMMP-8 hMMP-9 hMMP-13Example (nM) (nM) (nM) (nM) (nM) (nM)  4 >10,000 20.0 2.5 4a >10,000 0.224.0 2.2  5 4,850 0.35  6 >10,000 3,500 250  7 4,000 0.2 90.0 9.0 4.50.3  8 4,000 0.2 50.0 25.8 31.0 0.1  9 4,000 <0.1 55.0 8.0 200 <0.1 105,600 350 <0.1 10a <0.1 180 2.6 11 >10,000 0.1 225 39.0 24.0 0.5 123,400 800 12.3 245 11.4 13 880 1.9 0.4 14 >10,000 <0.1 30.0 34.0 161<0.1 15 >10,000 <0.1 140 241 286 <0.1

EXAMPLE 17 In Vivo Angiogenesis Assay

The study of angiogenesis depends on a reliable and reproducible modelfor the stimulation and inhibition of a neovascular response. Thecorneal micropocket assay provides such a model of angiogenesis in thecornea of a mouse. See, A Model of Angiogenesis in the Mouse Cornea;Kenyon, B M, et al., Investigative Ophthalmology & Visual Science, July1996, Vol. 37, No. 8.

In this assay, uniformly sized Hydron™ pellets containing bFGF andsucralfate are prepared and surgically implanted into the stroma mousecornea adjacent to the temporal limbus. The pellets are formed by makinga suspension of 20 μL sterile saline containing 10 μg recombinant bFGF,10 mg of sucralfate and 10 μL of 12 percent Hydron™ in ethanol. Theslurry is then deposited on a 10×10 mm piece of sterile nylon mesh.After drying, the nylon fibers of the mesh are separated to release thepellets.

The corneal pocket is made by anesthetizing a 7 week old C57Bl/6 femalemouse, then proptosing the eye with a jeweler's forceps. Using adissecting microscope, a central, intrastromal linear keratotomy ofapproximately 0.6 mm in length is performed with a #15 surgical blade,parallel to the insertion of the lateral rectus muscle. Using a modifiedcataract knife, a lamellar micropocket is dissected toward the temporallimbus. The pocket is extended to within 1.0 mm of the temporal limbus.A single pellet is placed on the corneal surface at the base of thepocket with a jeweler's forceps. The pellet is then advanced to thetemporal end of the pocket. Antibiotic ointment is then applied to theeye.

Mice are dosed on a daily basis for the duration of the assay. Dosing ofthe animals is based on bioavailability and overall potency of thecompound. an exemplary dose is 50 mg/kg bid, po. Neovascularization ofthe corneal stroma begins at about day three and is permitted tocontinue under the influence of the assayed compound until day five. Atday five, the degree of angiogenic inhibition is scored by viewing theneovascular progression with a slit lamp microscope.

The mice are anesthetized and the studied eye is once again proptosed.The maximum vessel length of neovascularization, extending from thelimbal vascular plexus toward the pellet is measured. In addition, thecontiguous circumferential zone of neovascularization is measured asclock hours, where 30 degrees of arc equals one clock hour. The area ofangiogenesis is calculated as follows.${area} = \frac{\left( {0.4 \times {clock}\quad {hours} \times 3.14 \times {vessel}\quad {length}\quad \left( {{in}\quad {mm}} \right)} \right)}{2}$

The studied mice are thereafter compared to control mice and thedifference in the area of neovascularization is recorded. A contemplatedcompound typically exhibits about 25 to about 75 percent inhibition,whereas the vehicle control exhibits zero percent inhibition.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The foregoing specific embodiments are, therefore,to be construed as merely illustrative, and not limitative of theremainder of the disclosure in any way whatsoever.

From the forgoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound or a salt thereof, wherein: thecompound or salt is characterizeable in that the compound or saltselectively inhibits in vitro activity of human MMP)-2, human MMP-3,and/or human MMP-13 over in vitro activity of human MMP-1; the compoundcorresponds in structure to Formula VII:

n is selected from the group consisting of zero, 1, and 2; W is—NR⁵COR⁶;R¹ is selected from the group consisting of cycloalkylene, arylene, andheteroarylene; R² is selected from the group consisting of alkyl,aralkyl, heteroaralkyl, cycloalkylalkyl, heterocycloalkylalkyl,hydroxycarbonylalkyl, aroylalkyl, and heteroaroylalkyl; R³ is selectedfrom the group consisting of hydrido, alkyl, aryl, aralkyl, thioalkyl,heteroaralkyl, heteroaryl, alkoxyalkoxyalkyl, trifluoromethylalkyl,alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxycarbonylalkyl,alkoxyalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylthioalkyl,arylthioalkyl, heteroarylthioalkyl, a sulfoxide of any saidthio-containing substituents, a sulfone of any said thio-containingsubstituents, —(CH₂)_(x)—C(O)NR¹¹R¹², and —(CH₂)_(y)—W¹; each x is aninteger from zero to 6; y is an integer from I to 6; R⁴ is selected fromthe group consisting of hydrido and C₁-C₄ alkyl; as to R⁵ and R⁶: R⁵ isselected from the group consisting of hydrido and C₁-C₄ alkyl; and R⁶ isselected from the group consisting of hydrido, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, and—(CH₂)_(x)—NR¹¹R¹², wherein: any aryl or heteroaryl of R⁶ is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halo, C₁-C₆ alkyl, C₁-C₄ alkoxy, nitro, cyano,hydroxy, carboxy, hydroxycarbonylalkyl, —(CH₂)_(x)—NR¹¹R¹²,trifluoromethyl, alkoxycarbonyl, aminocarbonyl, thio, alkylsulfonyl,carbonylamino, aminosulfonyl, alkylsulfonamino, alkoxyalkyl,cycloalkyloxy, alkylthioalkyl, and alkylthio, or R⁵ and R⁶, togetherwith the atoms to which they are bonded, form an optionally substituted5- or 7-membered cyclic amide or imide; as to each pair of R¹¹ and R¹²:R¹¹ and R¹² are independently selected from the group consisting ofhydrido, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,alkanoyl, aralkanoyl, and heteroaralkanoyl, or R¹¹ and R¹², togetherwith the atom to which they are bonded, form a 5- to 8-memberedheterocyclo or heteroaryl ring; R¹³ is selected from the groupconsisting of hydrido and C₁-C₆ alkyl; R¹⁴ is selected from the groupconsisting of hydrido, C₁-C₆ alkyl, optionally substituted aryl,optionally substituted arylalkyl, and tetrahydropyranyl; W¹ is selectedfrom the group consisting of —NR^(5a)COR^(6a), NR^(5a)S(O)_(z)R⁷,—NR^(5a)COOR⁸, —NR^(5a)CONR⁸R⁹, and NR¹¹R¹²; z is selected from thegroup consisting of zero, 1, and 2; as to R^(5a), R^(6a), R⁷, R⁸, andR⁹: R^(5a) is selected from the group consisting of hydrido and C₁-C₄alkyl, and R^(6a) is selected from the group consisting of hydrido,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, and—(CH₂)_(x)—NR¹¹R¹², R^(5a) and R^(6a), together with the atoms to whichthey are bonded, form an optionally substituted 5- or 7-membered cyclicamide or imide, R^(5a) is selected from the group consisting of hydridoand C₁-C₄ alkyl, and R⁷ is selected from the group consisting ofhydrido, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,alkylthioalkyl, and —(CH₂)_(x)—NR¹¹R¹², R^(5a) and R⁷, together with theatoms to which they are bonded, form an optionally substituted 5- or7-membered cyclic sulfonamide, R^(5a) is selected from the groupconsisting of hydrido and C₁-C₄ alkyl, and R⁸ and R⁹ are independentlyselected from the group consisting of hydrido, alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, and—(CH₂)_(x)—NR¹¹R¹², or R^(5a) is selected from the group consisting ofhydrido and C₁-C₄ alkyl, and R⁸ and R⁹, together with the atom to whichthey are bonded, form a 5- to 7-membered ring having no greater than onering atom selected from the group consisting of oxygen, nitrogen, andsulfur, with the remaining ring atoms being carbon; and any aryl orheteroaryl of R^(6a), R⁷, R⁸, or R⁹ is optionally substituted with oneor more substituents independently selected from the group consisting ofhalo, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, cyano, hydroxy, carboxy,hydroxycarbonylalkyl, —(CH₂)_(x)—NR¹¹R¹², trifluoromethyl,alkoxycarbonyl, aminocarbonyl, thio, alkylsulfonyl, carbonylamino,aminosulfonyl, alkylsulfonamino, alkoxyalkyl, cycloalkyloxy,alkylthioalkyl, and alkylthio.
 2. A compound or salt according to claim1, wherein n is
 2. 3. A compound or salt according to claim 1, whereinR¹ is arylene.
 4. A compound or a salt thereof, wherein: the compound orsalt is characterizeable in that the compound or salt selectivelyinhibits in vitro activity of human MMP-2, human MMP-3, and/or humanMMP-13 over in vitro activity of human MMP-1; the compound correspondsin structure to Formula I:

n is selected from the group consisting of zero, 1, and 2; W is—NR⁵COR⁶; R¹ is selected from the group consisting of cycloalkylene,arylene, and heteroarylene; R² is selected from the group consisting ofalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, heterocycloalkylalkyl,hydroxycarbonylalkyl, aroylalkyl, and heteroaroylalkyl; R³ is selectedfrom the group consisting of hydrido, alkyl, aryl, aralkyl, thioalkyl,heteroaralkyl, heteroaryl, alkoxyalkoxyalkyl, trifluoromethylalkyl,alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxycarbonylalkyl,alkoxyalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylthioalkyl,arylthioalkyl, heteroarylthioalkyl, a sulfoxide of any saidthio-containing substituents, a sulfone of any said thio-containingsubstituents, —(CH₂)_(x)—C(O)NR¹¹R¹², and —(CH₂)_(y)—W¹; each x is aninteger from zero to 6; y is an integer from 1 to 6; R⁴ is selected fromthe group consisting of hydrido and C₁-C₄ alkyl; as to R⁵ and R⁶: R⁵ isselected from the group consisting of hydrido and C₁-C₄ alkyl; and R⁶ isselected from the group consisting of hydrido, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, and—(CH₂)_(x)—NR¹¹R¹², wherein: any aryl or heteroaryl of R⁶ is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halo, C₁-C₆ alkyl, C₁-C₄ alkoxy, nitro, cyano,hydroxy, carboxy, hydroxycarbonylalkyl, —(CH₂)_(x)—NR¹¹R¹²,trifluoromethyl, alkoxycarbonyl, aminocarbonyl, thio, alkylsulfonyl,carbonylamino, aminosulfonyl, alkylsulfonamino, alkoxyalkyl,cycloalkyloxy, alkylthioalkyl, and alkylthio, or R⁵ and R⁶, togetherwith the atoms to which they are bonded, form an optionally substituted5- or 7-membered cyclic amide or imide; as to each pair of R¹¹ and R¹²:R¹¹ and R¹² are independently selected from the group consisting ofhydrido, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl,alkanoyl, aralkanoyl, and heteroaralkanoyl, or R¹¹ and R¹², togetherwith the atom to which they are bonded, form a 5 to 8-memberedheterocyclo or heteroaryl ring; and R¹³ is selected from the groupconsisting of hydrido and C₁-C₆ alkyl; W¹ is selected from the groupconsisting of —NR^(5a)COR^(6a), NR^(5a)S(O)_(z)R⁷, —NR^(5a)COOR⁸,—NR^(5a)CONR⁸R⁹, and —NR¹¹R¹²; z is selected from the group consistingof zero, 1, and 2; as to R^(5a), R^(6a), R⁷ R⁸, and R⁹: R^(5a) isselected from the group consisting of hydrido and C₁-C₄ alkyl, andR^(6a) is selected from the group consisting of hydrido, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, and—(CH₂)_(x)—NR¹¹R¹², R^(5a) and R^(6a), together with the atoms to whichthey are bonded, form an optionally substituted 5- or 7-membered cyclicamide or imide, R^(5a) is selected from the group consisting of hydridoand C₁-C₄ alkyl, and R⁷ is selected from the group consisting ofhydrido, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,alkylthioalkyl, and —(CH₂)_(x)—NR¹¹R¹², R^(5a) and R⁷, together with theatoms to which they are bonded, form an optionally substituted 5- or7-membered cyclic sulfonamide, R^(5a) is selected from the groupconsisting of hydrido and C₁-C₄ alkyl, and R⁸ and R⁹ are independentlyselected from the group consisting of hydrido, alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, and—(CH₂)_(x)—NR¹¹R¹², or R^(5a) is selected from the group consisting ofhydrido and C₁-C₄ alkyl, and R⁸ and R⁹, together with the atom to whichthey are bonded, form a 5- to 7-membered ring having no greater than onering atom selected from the group consisting of oxygen, nitrogen, andsulfur, with the remaining ring atoms being carbon; and any aryl orheteroaryl of R^(6a), R⁷, R⁸, or R⁹ is optionally substituted with oneor more substituents independently selected from the group consisting ofhalo, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, cyano, hydroxy, carboxy,hydroxycarbonylalkyl, —(CH₂)_(x)—NR¹¹R¹², trifluoromethyl,alkoxycarbonyl, aminocarbonyl, thio, alkylsulfonyl, carbonylamino,aminosulfonyl, alkylsulfonamino, alkoxyalkyl, cycloalkyloxy,alkylthioalkyl, and alkylthio.
 5. A compound or salt according to claim4, wherein n is
 2. 6. A compound or salt according to claim 5, whereinR¹ is arylene.
 7. A compound or salt according to claim 6, wherein R⁴ ishydrido.
 8. A compound or salt according to claim 4, wherein thecompound corresponds in structure to formula III:


9. A compound or salt according to claim 8, wherein R¹³ and R⁴ are bothhydrido.
 10. A compound or salt according to claim 8, wherein R⁴ ishydrido.
 11. A salt according to claim 10, wherein the salt correspondsin structure to the following formula:


12. A compound or salt according to claim 8, wherein R⁶ isheteroarylaryl.
 13. A compound or salt according to claim 10, whereinthe compound corresponds in structure to the following formula:


14. A process for treating a mammal having a condition associated withpathological matrix metalloprotease activity, wherein: the processcomprises administering a compound or a salt thereof in an MMPenzyme-inhibiting effective amount to the mammal; the compound or saltis characterizeable in that the compound or salt selectively inhibits invitro activity of human MMP-2, human MMP-3, and/or human MMP-13 over invitro activity of human MMP-1; the compound corresponds in structure toFormula I:

n is selected from the group consisting of zero, 1, and 2; W is—NR⁵COR⁶; R¹ is selected from the group consisting of cycloalkylene,arylene, and heteroarylene; R² is selected from the group consisting ofalkyl, aralkyl, heteroaralkyl, cycloalkylalkyl, heterocycloalkylalkyl,hydroxycarbonylalkyl, aroylalkyl, and heteroaroylalkyl; R³ is selectedfrom the group consisting of hydrido, alkyl, aryl, aralkyl, thioalkyl,heteroaralkyl, heteroaryl, alkoxyalkoxyalkyl, trifluoromethylalkyl,alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxycarbonylalkyl,alkoxyalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylthioalkyl,arylthioalkyl, heteroarylthioalkyl, a sulfoxide of any saidthio-containing substituents, a sulfone of any said thio-containingsubstituents, —(CH₂)_(x)—C(O)NR¹¹R¹², and —(CH₂)y—W¹, each x is aninteger from zero to 6; y is an integer from 1 to 6; R⁴ is selected fromthe group consisting of hydrido and C₁-C₄ alkyl; as to R⁵ and R⁶: R⁵ isselected from the group consisting of hydrido and C₁-C₄ alkyl; and R⁶ isselected from the group consisting of hydrido, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, and—(CH₂)_(x) 13 NR¹¹R¹², wherein: any aryl or heteroaryl group of R⁶ isoptionally substituted with one or more substituents independentlyselected from the group consisting of halo, C₁-C₆ alkyl, C₁-C₄ alkoxy,nitro, cyano, hydroxy, carboxy, hydroxycarbonylalkyl,—(CH₂)_(x)—NR¹¹R¹², trifluoromethyl, alkoxycarbonyl, aminocarbonyl,thio, alkylsulfonyl, carbonylamino, aminosulfonyl, alkylsulfonamino,alkoxyalkyl, cycloalkyloxy, alkylthioalkyl, and alkylthio, or R⁵ and R⁶,together with the atoms to which they are bonded, form an optionallysubstituted 5- or 7-membered cyclic amide or imide; asto each pair ofR¹¹ and R¹²: R¹¹ and R¹² are independently selected from the groupconsisting of hydrido, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, alkanoyl, aralkanoyl, and heteroaralkanoyl, or R¹¹ and R¹²,together with the atom to which they are bonded, form a 5 to 8-memberedheterocyclo or heteroaryl ring; and R¹³ is selected from the groupconsisting of hydrido and C₁-C₆ alkyl; W¹ is selected from the groupconsisting of —NR^(5a)COR^(6a), NR^(5a)S(O)_(z)R⁷, —NR^(5a)COOR⁸,—NR^(5a)CONR⁸R⁹, and —NR¹¹R¹²; z is selected from the group consistingof zero, 1, and 2; as to R^(5a), R^(6a), R⁷, R⁸ and R⁹: R^(5a) isselected from the group consisting of hydrido and C₁-C₄ alkyl, andR^(6a) is selected from the group consisting of hydrido, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, and—(CH₂)_(x)—NR¹¹R¹², R^(5a) and R^(6a), together with the atoms to whichthey are bonded, form an optionally substituted 5- or 7-membered cyclicamide or imide, R^(5a) is selected from the group consisting of hydridoand C₁-C₄ alkyl, and R⁷ is selected from the group consisting ofhydrido, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl,alkylthioalkyl, and —(CH₂)_(x)—NR¹¹R¹², R^(5a) and R⁷, together with theatoms to which they are bonded, form an optionally substituted 5- or7-membered cyclic sulfonamide, R^(5a) is selected from the groupconsisting of hydrido and C₁-C₄ alkyl, and R⁸ and R⁹ are independentlyselected from the group consisting of hydrido, alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, alkylthioalkyl, and—(CH₂)_(x)—NR¹¹R¹², or R^(5a) is selected from the group consisting ofhydrido and C₁-C₄ alkyl, and R⁸ and R⁹, together with the atom to whichthey are bonded, form a 5- to 7-membered ring having no greater than onering atom selected from the group consisting of oxygen, nitrogen, andsulfur, with the remaining ring atoms being carbon; and any aryl orheteroaryl of R^(6a), R⁷, R⁸, or R⁹ is optionally substituted with oneor more substituents independently selected from the group consisting ofhalo, C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, cyano, hydroxy, carboxy,hydroxycarbonylalkyl, —(CH₂)_(x)—NR¹¹R¹², trifluoromethyl,alkoxycarbonyl, aminocarbonyl, thio, alkylsulfonyl, carbonylamino,aminosulfonyl, alkylsulfonamino, alkoxyalkyl, cycloalkyloxy,alkylthioalkyl, and alkylthio.
 15. The process according to claim 14wherein n is
 2. 16. The process according to claim 14 wherein R¹ isarylene.
 17. The process according to claim 14, wherein said compoundcorresponds in structure to formula III:


18. The process according to claim 14, wherein said compound or salt isadministered a plurality of times.
 19. A compound or salt according toclaim 10 wherein the compound corresponds in structure to the followingformula:


20. A salt according to claim 10, wherein the salt corresponds instructure to the following formula:


21. A salt according to claim 10, wherein the salt corresponds instructure to the following formula:


22. A salt according to claim 10, wherein the salt corresponds instructure to the following formula:


23. A salt according to claim 10, wherein the salt corresponds instructure to the following formula:


24. A salt according to claim 10, wherein the salt corresponds instructure to the following formula:


25. A salt according to claim 10, wherein the salt corresponds instructure to the following formula:


26. A salt according to claim 10, wherein the salt corresponds instructure to the following formula:


27. A compound or salt according to claim 10, wherein the compoundcorresponds in structure to the following formula:


28. A compound or salt according to claim 10, wherein the compoundcorresponds in structure to the following formula:


29. A compound or salt according to claim 10, wherein the compoundcorresponds in structure to the following formula:


30. A compound or salt according to claim 10, wherein the compoundcorresponds in structure to the following formula:


31. A compound or salt according to claim 10, wherein the compoundcorresponds in structure to the following formula:


32. A compound or salt according to claim 10, wherein the compoundcorresponds in structure to the following formula:


33. A compound or salt according to claim 10, wherein the compoundcorresponding in structure to the following formula:


34. A compound or salt according to claim 10, wherein the compoundcorresponding to the following formula: